Embryology - User contributions [en-gb]

2017 Group Project 2

2017-10-26T03:11:21Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> <pubmed>2880702</pubmed> </ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> <pubmed> 12089378 </pubmed> </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> <pubmed> 3063284 </pubmed> </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref name="PMID28818273"><pubmed>28818273</pubmed></ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T03:08:50Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> <pubmed>2880702</pubmed> </ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> <pubmed> 3063284 </pubmed> </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref name="PMID28818273"><pubmed>28818273</pubmed></ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T03:08:24Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> <pubmed>2880702</pubmed> </ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> <pubmed> 3063284 </pubmed> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref name="PMID28818273"><pubmed>28818273</pubmed></ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T03:05:56Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> <pubmed>2880702</pubmed> </ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref name="PMID28818273"><pubmed>28818273</pubmed></ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T03:02:40Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> <pubmed>2880702</pubmed> </ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis <ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref name="PMID28818273"><pubmed>28818273</pubmed></ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref name="PMID28818273"><pubmed>28818273</pubmed></ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T03:00:05Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> <pubmed>2880702</pubmed> </ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T02:59:09Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> <pubmed>2880702</pubmed> <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T02:57:36Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> <pubmed>15172686 </pubmed> </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T02:54:06Z

Z5178275: /* References */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=
<references/>

2017 Group Project 2

2017-10-26T01:26:41Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
[[File:renal_corpuscle.png|500px|thumb|right|'''Figure 6.''' Diagram displaying the glomerulus]]
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle''' as shown in figure 6. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. Figure 6 displays the three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 7.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 8.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 9.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a hypothesis, that the use of high blood pressure (BHP2) mice can be used to examine the relationship between nephron endowment and hypertension.
<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
BHP2 mice is an old mouse model, and was already produced back in 1974. Back then the selective breed eight common mice strains and the off-spring was screened and selected based on their blood pressure phenotypes. This resulted in hypotensive BPL1 (low blood pressure), hypertensive BPH2 and normotensive BPN3 (normal blood pressure) mice. Therefore this model has hypertensive mice with an control hypotensive line. Much is known about the blood pressure in these mice, however little is known about the nephron number.
This model could therefore be used to examine relationship between nephron number and hypertension, because if Brenners hypothesis is true, then the BPH2 mice would have lower nephron number compared to the hypotensive mice <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref> . The model could also be used to examine the relationship between nephron number and glomerular diameter and volume, and see if the kidney compensate for low nephron number through this mechanism.
The model seems promising to get further evidence that support Brenners hypothesis.

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-26T00:47:12Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.
<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-26T00:42:32Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic waste from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.
<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-26T00:41:52Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. <ref> https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335 </ref> . This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> <pubmed>28818273</pubmed> </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> <pubmed>28818273</pubmed> </ref>
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.
<ref> <pubmed>28818273</pubmed> </ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-26T00:40:35Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure.<ref>https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335</ref>. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.
<ref> <pubmed>28818273</pubmed> </ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-26T00:33:28Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure.<ref>https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335</ref>. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension. <ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273 </ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-26T00:30:30Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure.<ref>https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335</ref>. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref>https://www.ncbi.nlm.nih.gov/pubmed/?term=A+novel+genetic+model+to+explore+the+Brenner+hypothesis%3A+Linking+nephron+endowment+and+number+with+hypertension.</ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref>https://www.ncbi.nlm.nih.gov/pubmed/?term=A+novel+genetic+model+to+explore+the+Brenner+hypothesis%3A+Linking+nephron+endowment+and+number+with+hypertension.</ref>
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/?term=A+novel+genetic+model+to+explore+the+Brenner+hypothesis%3A+Linking+nephron+endowment+and+number+with+hypertension.</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-26T00:29:00Z

Z5178275: /* Can hypertension be associated with nephron endowment? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure.<ref>https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/1.4.335</ref>. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time. <ref>https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis. <ref>https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T22:05:31Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702 </ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T21:55:20Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

As mentioned above, the kidneys fall under the renal system however this wiki page is solely dedicated to kidneys. If you would like more information on the renal system, please expand:
{| class="wikitable mw-collapsible mw-collapsed"
! General info on the renal system  
|-
|The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

'''Ureters''': A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

'''Bladder''': The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.

'''Urethra''': The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
|}

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | Week
! style="background:#f4a941" | Development
|-
| '''4 (early)''' || Pronephros begins (first stage of nephrogenesis)
|-
| '''4 (late)''' || Mesonephros begins (second stage of nephrogenesis)
|-
| '''5''' || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| '''6''' || Ascension of kidneys from pelvis area begins
|-
| '''8''' || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| '''9''' || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| '''10''' || Kidneys now ready to perform filtration
|-
| '''15''' || Renal vasculature development is completed
|-
| '''36''' || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|'''Postnatal''' || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

Before reading the steps below, it may be helpful to consult this video first.

<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

Notable genes and their roles:
{| class="wikitable"
! style="background:#f4a941" | Gene
! style="background:#f4a941" | Function
|-
|'''BF-2''' (transcription factor belonging to the Winged Helix family) || Regulates kidney stromal cell formation<ref>Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. and Lai, E. (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev. 10, 1467–1478.</ref>
|-
|'''Bmp-7''' (also known as OP-1) || Regulator of nephron maturation. Plays a role in the differentiation of metanephric mesenchyme.<ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
| '''FGF-2''' (fibroblast growth factor) || Produced by ureteric bud. Prevents mesenchyme apoptosis and induces regulation of transcription factor WT-1. FGF-2 also plays a role in tubulogenesis.<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
| '''GDNF''' (gilial cell derived neurotrophic factor) || Partners with RET to form the GDNF/RET pathway which is the primary signally complex that regulates growth of ureteric bud<ref>Pachnis, V., Mankoo, B. and Costantini, F. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017.</ref>
|-
|'''Hox genes'''|| The current understanding is that Hox genes provide the positional information during development.<ref>Krumlauf, R. (1994) Hox genes and vertebrate development. Cell 78, 191–201.</ref>
|-
| '''LIF''' (leukaemia inhibitory factor) || Combines with FGF-2 to form nephrons<ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>
|-
|'''p53''' (a tumor suppressive gene) || p53 is an important regulator of cell growth. In mice, it has been found that taking away p53 does not have any significant developmental effect, however over expression does. Too much p53 can result in a smaller kidney and therefore a smaller number of nephrons also.<ref>Godley, L.A., Kop, J.B., Eckhaus, M., Paglino, J.J., Owens, J. and Varmus, H.E. (1996) Wild-type-p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes Dev. 10, 836–850.</ref>
|-
| '''Wnt-4''' (of the Wnt gene family) || Regulator of nephron maturation. Wnt-4 is required for epithelium formation in the metanephros. <ref>Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683</ref>
|-
|''' WT-1''' || Important transcription factor that is essential during different stages of renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons. It also regulates other genes.<ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.
|}

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
{| class="wikitable"
! style="background:#f4a941" | Model
! style="background:#f4a941" | Description
|-
|'''Hoxb7/GFP transgenic mice'''|| The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702</ref>
|-
| '''Ksp-cadherin (Ksp1.3/BgEGFP) transgenic mouse model''' || Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref>http://jasn.asnjournals.org/content/13/7/1824.full.html</ref>
|-
|'''Sall-1 knock-in mice'''||This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref>https://www.ncbi.nlm.nih.gov/pubmed/15172686</ref>
|}

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|'''Isthmus'''
| A narrow organ, passage, or piece of tissue connecting two larger parts.
|-
|''' Metanephric blastema'''
| Described as a cloud of mesenchymal tissue, its cells migrate and grow in the traditional kidney bean shape.The metanephric blastema gives rise to the glomeruli and Bowman's capsule, structures which interact in order to eventually form the nephron.
|-bgcolor="FAF5FF"
|'''Mesenchyme/Mesenchymal tissue'''
| A loosely organized, mainly mesodermal embryonic tissue containing unspecialised cells which develops into connective and skeletal tissues, including blood and lymph.
|-
|'''Parenchyma'''
| The functional tissue of an organ as distinguished from the connective and supporting tissue.
|-bgcolor="FAF5FF"
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|-
|'''Retroperitoneum'''
| The space between the peritoneum and the posterior abdominal wall that contains especially the kidneys and associated structures, the pancreas, and part of the aorta and inferior vena cava.
|-bgcolor="FAF5FF"
|'''Ureteric bud'''
| Dorsal outgrowth of the nephric/mesonephric/Wolffian duct which goes on to form the ureters and collecting tubules of the kidneys.
|-
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:53:39Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:52:37Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:52:08Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:51:27Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:51:01Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:50:22Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes the technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:46:42Z

Z5178275: /* Can hypertension be associated with nephron number? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron endowment?===
Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development.
Back in 1988, Doctor Barry Brenner hypothesized that there is an inverse relationship between nephron endowment and the risk of developing hypertension. He suggested that the kidney compensate for a reduction in nephron number by increasing the glomerular surface, which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. This hypothesis is based on a study he conducted in hypertensive patients and many more have supported Brenner’s hypothesis. These studies have all shown an association between hypertension and low nephron number. However, no correlation has been demonstrated, because most kidney have been obtained from death individuals. So blood pressure and nephron number has not been measured at the same time.
Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many of them.
Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate.
So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potentially be used to explore the relationship between nephron endowment and hypertension.<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:39:14Z

Z5178275: /* Can hypertension be associated with nephron number? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

Nephron endowment is the total number of nephrons an individual has at birth – and only depends on embryonic development. Back in 1988 Brenner hypothesized that there is an inverse relationship between total nephron number at birth and the risk of developing hypertension. This hypothesis is based on a study he conducted in hypertensive patients. He suggested that the kidney compensate for the reduction in nephron number by increasing the glomerular surface which in the long run contributes to hypertension because the sodium and fluid retention is increased. These changes then lead to an increase in arterial and glomerular capillary pressure, glomerular hyper filtration and injury which ultimately increase arterial pressure. Many studies have supported Brenner’s hypothesis by showing an association between hypertension and low nephron number. However, no correlation has been show, because most kidney have been obtained from death individuals so you have not been able to measure blood pressure and count the nephron number at the same time. Also, the methods to measure nephron number in humans have been complicated, not so accurate and there are not very many. (kilde 13, 14 og 15) Often you would measure the nephron number indirect by measuring kidney mass or volume, or you would do a kidney biopsy even though it only gives an estimate. So, some of the more current research has been to develop an experimental model with reduced nephron number to allow direct testing of Brenners hypothesis and see if there is evidence for this hypothesis.
One recent study has made a propose on a mouse model which can potential be used to explore the relationship between nephron endowment and hypertension.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T13:38:27Z

Z5178275: /* Can kidney disease be associated with nephron number? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. As shown in figure 1, they are typical located between the transverse processes from Thoracic 12 (T12) to Lumbar 3 (L3) of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla''' as shown in figure 2. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue. Before reading the steps below, it may be helpful to consult this video first.
<html5media height="300" width="500">https://www.youtube.com/watch?v=81yCpyF2VhQ</html5media> <ref> Embryology of the Kidney (Easy to Understand). (2016). Retrieved October 26, 2017, from https://www.youtube.com/watch?v=Fir-v6EoZNE </ref>

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

===== 1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
{{Renal overview movie}}
Here is an animation showing the renal development described in this section.

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]
{{Nephron movie}}
Here is a quick animation depicting nephron development. The steps are summarised below.

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===

During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands. During the process of ascension, the kidneys also develop their vasculature as depicted in the animation.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

{{Renal vascular movie}}
This animation depicts the kidneys during ascension. You can also see vasculature development.

===Renal vasculature===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. During ascension, the kidneys receive blood from the dorsal aorta. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Horseshoe kidney (fusion of two kidneys during development)

* Wilms tumours (kidney cancer)

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can hypertension be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T10:19:45Z

Z5178275: /* Can kidney disease be associated with nephron number? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

<ref> https://www.ncbi.nlm.nih.gov/pubmed/28818273</ref>

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T09:51:57Z

Z5178275: /* Clock genes */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud shapes into the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T09:23:28Z

Z5178275: /* Current Research */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct, also known as the Wolffian duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

==Clock genes==

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T09:19:20Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects<ref>https://www.kidney.org/atoz/content/detectkid</ref> such as horseshoe kidney, Wilms' tumor and renal genesis. Research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

Stages in nephron formation:

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* '''Ksp-cadherin (Ksp1.3/BgEGFP ) transgenic mouse model'''. Ksp-cadherin is a tissue-specific cell adhesion molecule which is only expressed in tubular epithelial cells in the kidney and developing genitourinary tract. It is therefore a good model to visualize the ureteric bud, Wolffian duct, Müllerian duct, and developing tubules in the mesonephros and metanephros during development . <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* '''Sall-1 knock-in mice'''. This model uses GFP to visualize the ''Sall1'' gene expression, which is expressed in metanephric mesenchyme prior to bud invasion and in cells of mesenchymal origin (glomerular, proximal and distal tubule epithelia). This model has been used together with other techniques to determine which genes are expressed in the metanephric mesenchyme during development. <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T08:20:49Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects. <ref>https://www.kidney.org/atoz/content/detectkid</ref> The reason as to why this occurs is not known. However, research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
* FoxD1 knock-in mice in which GFP marks stromal cells <ref>https://www.ncbi.nlm.nih.gov/pubmed/15634693</ref>
* NPHS1 transgenics in which GFP marks podocytes (Eremina et al. 2002) <ref>https://www.ncbi.nlm.nih.gov/pubmed/11856786</ref>
* Ksp-cadherin (Ksp1.3/BgEGFP ) transgenics in which GFP marks the UB and tubules <ref> http://jasn.asnjournals.org/content/13/7/1824.full.html </ref>
* Tamm Horsfall protein transgenics in which GFP marks the thick ascending limb of the loop of Henle and early distal tubules <ref>https://www.ncbi.nlm.nih.gov/pubmed/11880321</ref>
* Sall-1 knock-in mice in which GFP marks the mesenchyme, nephron structures and cortical stroma <ref> https://www.ncbi.nlm.nih.gov/pubmed/15172686 </ref>

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T06:50:53Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects. <ref>https://www.kidney.org/atoz/content/detectkid</ref> The reason as to why this occurs is not known. However, research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* '''Hoxb7/GFP transgenic mice'''. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
*

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T06:49:34Z

Z5178275: /* Animal Models */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects. <ref>https://www.kidney.org/atoz/content/detectkid</ref> The reason as to why this occurs is not known. However, research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice.
To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) or LacZ is used. Using knock-out mice with a reporter gene makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead. The most commonly used method to create conditional knock-out mice is the use of Cre/loxP recombination.

Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.'

Below we have listed some of the transgenic mouse models which have been used to detect and visualize different kidney structures during development:
* Hoxb7/GFP transgenic mice. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref> and is one of the best known reporter mouse model. In this mouse model, the GFP is under the control of Hoxb7 promotor, and it is used to examine the genetic control of renal branching morphogenesis, therefore allowing visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter) <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880702/</ref>
*

Other promotors has been used as well like FoxD1, NPHS1, Ksp-cadherin, Tamm Horsfall protein and Sa
It is also possible to intercross a Hoxv7/GFP transgenic mouse with a genetically altered mice to detect and follow a protein of interest in a
If one wishes to visualize the progression of two or more kidney genes at the same time, then inter crossing of reporter mice with different variants of fluorescent reporter proteins can be used. A mice model for this purpose has been developed by Hadjantonakis et al. in 2002. In figure ...
To visualize the progression of two or more kidney genes in combination, intercrosses of reporter mice carrying spectral-variant fluorescent reporters (mRFLP, ECFP, EYFP) (Hadjantonakis et al. 2002, 2003; Long et al. 2005) can be undertaken. Reporter mouse lines can also be intercrossed with genetically altered mice to allow the researcher to follow the movement of a particular marked cell type in a mutant context. For example, the Hoxb7/GFP transgenic mouse line has been intercrossed with Foxd1 null-mutant mice to analyse the effects of the loss of Foxd1 on the branching pattern of the ureteric tree ( Levinson et al. 2005). Some examples of reporter mice expressing GFP in embryonic kidney cell types include the Hoxb7/GFP transgenic mice, as mentioned above, FoxD1 knock-in mice in which GFP marks stromal cells (Levinson et al. 2005), NPHS1 transgenics in which GFP marks podocytes (Eremina et al. 2002), Ksp-cadherin (Ksp1.3/BgEGFP ) transgenics in which GFP marks the UB and tubules (Shao et al. 2002), Tamm Horsfall protein transgenics in which GFP marks the thick ascending limb of the loop of Henle and early distal tubules (Zhu et al. 2002), and Sall-1 knock-in mice in which GFP marks the mesenchyme, nephron structures and cortical stroma (Takasato et al. 2004).

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-25T06:10:16Z

Z5178275: /* Can kidney disease be associated with nephron number? */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.

Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.<ref>Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011). Human nephron number: implications for health and disease. ''Pediatrics Nephrology'' 9: 1529-1533. doi: 10.1007/s00467-011-1843-8</ref>

It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects. <ref>https://www.kidney.org/atoz/content/detectkid</ref> The reason as to why this occurs is not known. However, research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.'''Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.'''A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells <ref>Costantini F, Kopan R (2010). Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. ''Science Direct'' 18: 698-712. doi: 10.1016/j.devcel.2010.04.008</ref>. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime. <ref>Barker N, Bartfeld S, Clevers H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. ''Cell Stem Cell'' 7: 656–670.</ref> Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C, Borodo K, Charles N, Herzlinger DA (2004). Morphometric index of the developing murine kidney. ''Developmental Dynamics'' 231: 601–608.</ref>

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. <ref>Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. ''Cell'' 99: 377–386.</ref>

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). WT-1 is required for early kidney development. ''Cell'' 74: 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. <ref>Blakemore C, Jennett S (2001). Kidneys. ''The Oxford Companion to the Body''.</ref> A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction <ref>Saeed K (2012). Renal infarction. ''International Journal of Nephrology and Renovascular Disease'' 5: 119-123.</ref>, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. <ref>Del PF, Mariotti A, Ilardi M, Messina FR, Afeltra A, Amoroso A (1999). Kidney vasculogenesis and angiogenesis: role of vascular endothelial growth factor. ''European Review for Medical and Pharmacological Sciences'' 3: 149-153.</ref>

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. <ref>Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD (2014). The glomerulus: the sphere of influence. ''Clinical Journal of the American Society of Nephrology'' 9: 1461-1469. doi: 10.2215/CJN.09400913.</ref>

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''<ref>Barajas L (1979). Anatomy of the juxtaglomerular apparatus. ''American Journal of Physiology'' 237: 333-343.</ref>

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop<ref>Persson AE, Ollerstam A, Liu R, Brown R (2004). Mechanisms for macula dense cell release of renin. ''Acta Physiologica Scandinavica'' 181: 471-474.</ref>

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.<ref>Ito S (1997). Kidney and hypertension: role of the juxtaglomerular apparatus. ''The Tohoku Journal of Experimental Medicine'' 181: 411-429.</ref>

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.<ref>Fyhrquist F, Saijonmaa O (2008). Renin-angiotensin system revisited. ''Journal of Internal Medicine'' 264: 224-236.</ref>

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM (2008). MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. ''Pediatric Nephrology'' 23: 1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R (2014). Molecular mechanisms of epithelial–mesenchymal transition. ''Nature Reviews Molecular Cell Biology'' 3: 178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, Parreira KS, Devuyst O, Caplanusi A, N'kuli F, Marien B, Van DSP, Alves PM, Verroust P, Christensen EI, Terzi F, Matter K, Balda MS, Pierre CE, Courtoy PJ (2010). ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. ''Journal of the American Society of Nephrology'' 3: 478–488. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. ''Journal of Clinical Investigation'' 6: 1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004). Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. ''Journals of the American Society of Nephrology'' 5:1232–1243. doi: 10.1097/01.ASN.0000123690.75029.3F</ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. ''Anti-Cancer Agents in Medicinal Chemistry'' 13: 70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF (2004). Overview of general physiologic features and functions of vitamin D. ''The American Journal of Clinical Nutrition'' 80: 1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002). 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. ''Journal of Clinical Investigation'' 2: 229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

Common congenital kidney defects include:

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL (1992).''Clinically Oriented Anatomy'', ed 3: p223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K (2002). Morphological study of a horseshoe kidney with special reference to the vascular system. ''Anatomical Science International'' 77: 134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff AM (2012). Wilms Tumor. ''Advances in Pediatrics'' 59: 247–267. doi: 10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. ''Cell'' 60: 509–520.</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Robson WL, Leung AK, Rogers RC (1995). Unilateral renal agencies. ''Advances in Pediatrics'' 42: 575-592.</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS (2008). Renal tract malformations: perspectives for nephrologists. ''Nature Clinical Practice Nephrology'' 4: 312-325</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, Soran M, Noyan A, Anarat A (2005). Associated anomalies in children with congenital solitary functioning kidney. ''Pediatrics Surgery International'' 21: 456-459.</ref>

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
----
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice. To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) is used. Using knock-out mice with a reporter gene like GFP makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead.

One of the more common methods to create conditional knock-out mice is the use of Cre/loxP recombination.
Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>Sauer B, Henderson N (1988). Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. ''Proceedings of the National Academy of Sciences'' 85: 5166-5170.</ref>.
Using this method it has been possible to identify several kidney-specific promoters.

==Hoxb7/GFP transgenic mouse model==
The best known reporter mouse model used for studying kidney development is the Hoxb7/GFP transgenic mice. The model was developed in 1999 by Srinivas et al. <ref>Srinivas S, Goldberg MR, Watanabe T, D'Agati V, al-Awqati Q, Costantini F (1999). Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. ''Developmental Genetics'' 24: 241-251.</ref>
In this mouse model, the GFP is under the control of HoxB7 promotor, and this allows visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter).

=Current Research=
----
===Can kidney disease be associated with nephron number?===
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273

===Kidney stem cells===
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. <ref>Kitamura S, Sakurai H, Makino H (2015). Single adult kidney stem/ progenitor cells reconstitute three-dimensional nephron structures in vitro. ''Stem Cells Journals'' 33: 774-784. doi: 10.1002/stem.1891</ref>

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-24T11:12:31Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs that play an important role in the renal system (also known as the urinary system). In the womb, the placenta is responsible for maintaining balance of water, nutrients, ion levels, etc. However, after birth, this responsibility is given to the kidneys. As such, they are vital for the everyday functions of the human body as they are the unit responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. The by-product of this process is urine, and it is excreted from the kidneys into the ureters which then deliver the urine to the urinary bladder.

Filtration is carried out in what is called the "nephron". In humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million. However, a typical kidney usually has approximately 900,000 to 1 million nephrons. Nephrons are the functional units of kidneys and are independent of each other.
<ref>https://www.ncbi.nlm.nih.gov/pubmed/21604189</ref>

Kidney development in the embryo is known as nephrogenesis and has three stages: pronephros, mesonephros and metanephros. This process typically begins in week 4 of gestation and ends in week 36. About 1 in 500 babies are born with a kidney problem due to developmental abnormalities. <ref>https://www.kidney.org/atoz/content/detectkid</ref>

Developmentally, they arise from the intermediate mesoderm.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.''' Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.''' A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic duct starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells[1]. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

[1]http://www.sciencedirect.com/science/article/pii/S1534580710002078

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime <ref>Barker, N., Bartfeld, S., and Clevers, H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell. 7: 656–670 </ref>. Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C., Borodo K., Charles N., Herzlinger D. A. (2004). Morphometric index of the developing murine kidney. Dev. Dyn. 231, 601–608</ref>.

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days <ref>Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., and Oliver, J.A. (1999b) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. Cell 99, 377–386.</ref>.

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg, J.A., Sariola, H., Loring, J.M., Maeda, M., Pelletier, J., Housman, D., and Jaenisch, R. (1993). WT-1 is required for early kidney development. Cell 74, 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders.

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function.

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''.

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop.

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM. MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. Pediatr Nephrol. 2008;23:1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;3:178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, et al. ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. J Am Soc Nephrol. 2010;3:478–88. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. J Clin Invest. 6:1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, et al (2004) Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol. 5:1232–43. doi: 10.1097/01.ASN.0000123690.75029.3F </ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. Ant. Canc. Ag Med. Chem. 13:70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 2002;2:229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

''Common congenital kidney defects include:''

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL: Clinically Oriented Anatomy, ed 3. Baltimore, Williams & Wilkins, 1992, p 223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K: Morphological study of a horseshoe kid- ney with special reference to the vascular system. Anat Sci Int 2002;77:134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff, A. M. (2012). Wilms Tumor. Advances in Pediatrics, 59(1), 247–267. http://doi.org/10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call K. M. et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60, 509–20 (1990)</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Paolo Volpe, Valentina De Robertis, Nicola Volpe Unilateral renal agenesis, Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, www.VISUOG.org, 30th of March, 2013</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS. Renal tract malformations: perspectives for nephrologists, Nat Clin Pract Nephrol , 2008, vol. 4 (pg. 312-325)</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, et al. . Associated anomalies in children with congenital solitary functioning kidney, Pediatr Surg Int , 2005, vol. 21 (pg. 456-459)</ref>.

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Animal Models=
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice. To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) is used. Using knock-out mice with a reporter gene like GFP makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead.

One of the more common methods to create conditional knock-out mice is the use of Cre/loxP recombination.
Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC281709/ </ref>.
Using this method it has been possible to identify several kidney-specific promoters.

== Hoxb7/GFP transgenic mouse model ==
The best known reporter mouse model used for studying kidney development is the Hoxb7/GFP transgenic mice. The model was developed in 1999 by Srinivas et al. <ref> https://www.ncbi.nlm.nih.gov/pubmed/10322632?dopt=Abstract </ref>
In this mouse model, the GFP is under the control of HoxB7 promotor, and this allows visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter).

=Current Research=
----
==Can kidney disease be associated with nephron number?==
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273
[[User:Z5017644|Z5017644]] ([[User talk:Z5017644|talk]]) 16:50, 31 August 2017 (AEST)

=Questions for the future=
----
==Kidney stem cells==
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro.

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-24T08:50:17Z

Z5178275: /* Glossary of terms */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs that play an important role in the renal system (also known as the urinary system). In the womb, the placenta is responsible for maintaining balance of water, nutrients, ion levels, etc. However, after birth, this responsibility is given to the kidneys. As such, they are vital for the everyday functions of the human body as they are the unit responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. The by-product of this process is urine, and it is excreted from the kidneys into the ureters which then deliver the urine to the urinary bladder.

Filtration is carried out in what is called the "nephron". In humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million. However, a typical kidney usually has approximately 900,000 to 1 million nephrons. Nephrons are the functional units of kidneys and are independent of each other.
<ref>https://www.ncbi.nlm.nih.gov/pubmed/21604189</ref>

Kidney development in the embryo is known as nephrogenesis and has three stages: pronephros, mesonephros and metanephros. This process typically begins in week 4 of gestation and ends in week 36. About 1 in 500 babies are born with a kidney problem due to developmental abnormalities. <ref>https://www.kidney.org/atoz/content/detectkid</ref>

Developmentally, they arise from the intermediate mesoderm.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.''' Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.''' A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic duct starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells[1]. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

[1]http://www.sciencedirect.com/science/article/pii/S1534580710002078

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime <ref>Barker, N., Bartfeld, S., and Clevers, H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell. 7: 656–670 </ref>. Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C., Borodo K., Charles N., Herzlinger D. A. (2004). Morphometric index of the developing murine kidney. Dev. Dyn. 231, 601–608</ref>.

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days <ref>Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., and Oliver, J.A. (1999b) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. Cell 99, 377–386.</ref>.

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg, J.A., Sariola, H., Loring, J.M., Maeda, M., Pelletier, J., Housman, D., and Jaenisch, R. (1993). WT-1 is required for early kidney development. Cell 74, 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders.

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function.

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''.

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop.

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM. MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. Pediatr Nephrol. 2008;23:1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;3:178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, et al. ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. J Am Soc Nephrol. 2010;3:478–88. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. J Clin Invest. 6:1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, et al (2004) Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol. 5:1232–43. doi: 10.1097/01.ASN.0000123690.75029.3F </ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. Ant. Canc. Ag Med. Chem. 13:70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 2002;2:229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

''Common congenital kidney defects include:''

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL: Clinically Oriented Anatomy, ed 3. Baltimore, Williams & Wilkins, 1992, p 223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K: Morphological study of a horseshoe kid- ney with special reference to the vascular system. Anat Sci Int 2002;77:134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff, A. M. (2012). Wilms Tumor. Advances in Pediatrics, 59(1), 247–267. http://doi.org/10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call K. M. et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60, 509–20 (1990)</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Paolo Volpe, Valentina De Robertis, Nicola Volpe Unilateral renal agenesis, Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, www.VISUOG.org, 30th of March, 2013</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS. Renal tract malformations: perspectives for nephrologists, Nat Clin Pract Nephrol , 2008, vol. 4 (pg. 312-325)</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, et al. . Associated anomalies in children with congenital solitary functioning kidney, Pediatr Surg Int , 2005, vol. 21 (pg. 456-459)</ref>.

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Current Research=
----
==Can kidney disease be associated with nephron number?==
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273
[[User:Z5017644|Z5017644]] ([[User talk:Z5017644|talk]]) 16:50, 31 August 2017 (AEST)

=Questions for the future=
----
==Kidney stem cells==
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro.

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|}

=References=

2017 Group Project 2

2017-10-24T08:50:01Z

Z5178275: /* Glossary of terms */

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs that play an important role in the renal system (also known as the urinary system). In the womb, the placenta is responsible for maintaining balance of water, nutrients, ion levels, etc. However, after birth, this responsibility is given to the kidneys. As such, they are vital for the everyday functions of the human body as they are the unit responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. The by-product of this process is urine, and it is excreted from the kidneys into the ureters which then deliver the urine to the urinary bladder.

Filtration is carried out in what is called the "nephron". In humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million. However, a typical kidney usually has approximately 900,000 to 1 million nephrons. Nephrons are the functional units of kidneys and are independent of each other.
<ref>https://www.ncbi.nlm.nih.gov/pubmed/21604189</ref>

Kidney development in the embryo is known as nephrogenesis and has three stages: pronephros, mesonephros and metanephros. This process typically begins in week 4 of gestation and ends in week 36. About 1 in 500 babies are born with a kidney problem due to developmental abnormalities. <ref>https://www.kidney.org/atoz/content/detectkid</ref>

Developmentally, they arise from the intermediate mesoderm.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.''' Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.''' A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic duct starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells[1]. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

[1]http://www.sciencedirect.com/science/article/pii/S1534580710002078

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime <ref>Barker, N., Bartfeld, S., and Clevers, H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell. 7: 656–670 </ref>. Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C., Borodo K., Charles N., Herzlinger D. A. (2004). Morphometric index of the developing murine kidney. Dev. Dyn. 231, 601–608</ref>.

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days <ref>Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., and Oliver, J.A. (1999b) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. Cell 99, 377–386.</ref>.

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg, J.A., Sariola, H., Loring, J.M., Maeda, M., Pelletier, J., Housman, D., and Jaenisch, R. (1993). WT-1 is required for early kidney development. Cell 74, 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders.

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function.

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''.

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop.

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM. MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. Pediatr Nephrol. 2008;23:1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;3:178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, et al. ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. J Am Soc Nephrol. 2010;3:478–88. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. J Clin Invest. 6:1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, et al (2004) Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol. 5:1232–43. doi: 10.1097/01.ASN.0000123690.75029.3F </ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. Ant. Canc. Ag Med. Chem. 13:70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 2002;2:229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

''Common congenital kidney defects include:''

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL: Clinically Oriented Anatomy, ed 3. Baltimore, Williams & Wilkins, 1992, p 223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K: Morphological study of a horseshoe kid- ney with special reference to the vascular system. Anat Sci Int 2002;77:134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff, A. M. (2012). Wilms Tumor. Advances in Pediatrics, 59(1), 247–267. http://doi.org/10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call K. M. et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60, 509–20 (1990)</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Paolo Volpe, Valentina De Robertis, Nicola Volpe Unilateral renal agenesis, Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, www.VISUOG.org, 30th of March, 2013</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS. Renal tract malformations: perspectives for nephrologists, Nat Clin Pract Nephrol , 2008, vol. 4 (pg. 312-325)</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, et al. . Associated anomalies in children with congenital solitary functioning kidney, Pediatr Surg Int , 2005, vol. 21 (pg. 456-459)</ref>.

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Current Research=
----
==Can kidney disease be associated with nephron number?==
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273
[[User:Z5017644|Z5017644]] ([[User talk:Z5017644|talk]]) 16:50, 31 August 2017 (AEST)

=Questions for the future=
----
==Kidney stem cells==
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro.

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|''' 6a'''
| 6b
|--bgcolor="FAF5FF"
|}

=References=

2017 Group Project 2

2017-10-24T08:48:53Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs that play an important role in the renal system (also known as the urinary system). In the womb, the placenta is responsible for maintaining balance of water, nutrients, ion levels, etc. However, after birth, this responsibility is given to the kidneys. As such, they are vital for the everyday functions of the human body as they are the unit responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. The by-product of this process is urine, and it is excreted from the kidneys into the ureters which then deliver the urine to the urinary bladder.

Filtration is carried out in what is called the "nephron". In humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million. However, a typical kidney usually has approximately 900,000 to 1 million nephrons. Nephrons are the functional units of kidneys and are independent of each other.
<ref>https://www.ncbi.nlm.nih.gov/pubmed/21604189</ref>

Kidney development in the embryo is known as nephrogenesis and has three stages: pronephros, mesonephros and metanephros. This process typically begins in week 4 of gestation and ends in week 36. About 1 in 500 babies are born with a kidney problem due to developmental abnormalities. <ref>https://www.kidney.org/atoz/content/detectkid</ref>

Developmentally, they arise from the intermediate mesoderm.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.''' Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.''' A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic duct starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells[1]. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

[1]http://www.sciencedirect.com/science/article/pii/S1534580710002078

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime <ref>Barker, N., Bartfeld, S., and Clevers, H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell. 7: 656–670 </ref>. Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C., Borodo K., Charles N., Herzlinger D. A. (2004). Morphometric index of the developing murine kidney. Dev. Dyn. 231, 601–608</ref>.

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days <ref>Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., and Oliver, J.A. (1999b) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. Cell 99, 377–386.</ref>.

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg, J.A., Sariola, H., Loring, J.M., Maeda, M., Pelletier, J., Housman, D., and Jaenisch, R. (1993). WT-1 is required for early kidney development. Cell 74, 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders.

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function.

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''.

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop.

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM. MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. Pediatr Nephrol. 2008;23:1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;3:178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, et al. ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. J Am Soc Nephrol. 2010;3:478–88. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. J Clin Invest. 6:1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, et al (2004) Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol. 5:1232–43. doi: 10.1097/01.ASN.0000123690.75029.3F </ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. Ant. Canc. Ag Med. Chem. 13:70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 2002;2:229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

''Common congenital kidney defects include:''

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL: Clinically Oriented Anatomy, ed 3. Baltimore, Williams & Wilkins, 1992, p 223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K: Morphological study of a horseshoe kid- ney with special reference to the vascular system. Anat Sci Int 2002;77:134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff, A. M. (2012). Wilms Tumor. Advances in Pediatrics, 59(1), 247–267. http://doi.org/10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call K. M. et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60, 509–20 (1990)</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Paolo Volpe, Valentina De Robertis, Nicola Volpe Unilateral renal agenesis, Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, www.VISUOG.org, 30th of March, 2013</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS. Renal tract malformations: perspectives for nephrologists, Nat Clin Pract Nephrol , 2008, vol. 4 (pg. 312-325)</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, et al. . Associated anomalies in children with congenital solitary functioning kidney, Pediatr Surg Int , 2005, vol. 21 (pg. 456-459)</ref>.

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Current Research=
----
==Can kidney disease be associated with nephron number?==
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273
[[User:Z5017644|Z5017644]] ([[User talk:Z5017644|talk]]) 16:50, 31 August 2017 (AEST)

=Questions for the future=
----
==Kidney stem cells==
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro.

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|''' 6a'''
| 6b
|--bgcolor="FAF5FF"
|''' 7a'''
| 7b
|-
|''' 8a'''
| 8b
|--bgcolor="FAF5FF"
|''' 9a'''
| 9b
|-
|''' 10a'''
| 10b
|--bgcolor="FAF5FF"
|''' 11a'''
| 11b
|-
|''' 12a'''
| 12b
|--bgcolor="FAF5FF"
|''' 13a'''
| 13b
|}

=References=

2017 Group Project 2

2017-10-24T08:48:29Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs that play an important role in the renal system (also known as the urinary system). In the womb, the placenta is responsible for maintaining balance of water, nutrients, ion levels, etc. However, after birth, this responsibility is given to the kidneys. As such, they are vital for the everyday functions of the human body as they are the unit responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. The by-product of this process is urine, and it is excreted from the kidneys into the ureters which then deliver the urine to the urinary bladder.

Filtration is carried out in what is called the "nephron". In humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million. However, a typical kidney usually has approximately 900,000 to 1 million nephrons. Nephrons are the functional units of kidneys and are independent of each other.
<ref>https://www.ncbi.nlm.nih.gov/pubmed/21604189</ref>

Kidney development in the embryo is known as nephrogenesis and has three stages: pronephros, mesonephros and metanephros. This process typically begins in week 4 of gestation and ends in week 36. About 1 in 500 babies are born with a kidney problem due to developmental abnormalities. <ref>https://www.kidney.org/atoz/content/detectkid</ref>

Developmentally, they arise from the intermediate mesoderm.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.''' Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.''' A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic duct starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells[1]. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

[1]http://www.sciencedirect.com/science/article/pii/S1534580710002078

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime <ref>Barker, N., Bartfeld, S., and Clevers, H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell. 7: 656–670 </ref>. Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C., Borodo K., Charles N., Herzlinger D. A. (2004). Morphometric index of the developing murine kidney. Dev. Dyn. 231, 601–608</ref>.

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days <ref>Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., and Oliver, J.A. (1999b) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. Cell 99, 377–386.</ref>.

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg, J.A., Sariola, H., Loring, J.M., Maeda, M., Pelletier, J., Housman, D., and Jaenisch, R. (1993). WT-1 is required for early kidney development. Cell 74, 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders.

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function.

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''.

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop.

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM. MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. Pediatr Nephrol. 2008;23:1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;3:178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, et al. ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. J Am Soc Nephrol. 2010;3:478–88. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. J Clin Invest. 6:1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, et al (2004) Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol. 5:1232–43. doi: 10.1097/01.ASN.0000123690.75029.3F </ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. Ant. Canc. Ag Med. Chem. 13:70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 2002;2:229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

''Common congenital kidney defects include:''

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL: Clinically Oriented Anatomy, ed 3. Baltimore, Williams & Wilkins, 1992, p 223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K: Morphological study of a horseshoe kid- ney with special reference to the vascular system. Anat Sci Int 2002;77:134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff, A. M. (2012). Wilms Tumor. Advances in Pediatrics, 59(1), 247–267. http://doi.org/10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call K. M. et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60, 509–20 (1990)</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Paolo Volpe, Valentina De Robertis, Nicola Volpe Unilateral renal agenesis, Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, www.VISUOG.org, 30th of March, 2013</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS. Renal tract malformations: perspectives for nephrologists, Nat Clin Pract Nephrol , 2008, vol. 4 (pg. 312-325)</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, et al. . Associated anomalies in children with congenital solitary functioning kidney, Pediatr Surg Int , 2005, vol. 21 (pg. 456-459)</ref>.

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Current Research=
----
==Can kidney disease be associated with nephron number?==
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273
[[User:Z5017644|Z5017644]] ([[User talk:Z5017644|talk]]) 16:50, 31 August 2017 (AEST)

=Questions for the future=
----
==Kidney stem cells==
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro.

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|''' 6a'''
| 6b
|--bgcolor="FAF5FF"
|''' 7a'''
| 7b
|-
|''' 8a'''
| 8b
|--bgcolor="FAF5FF"
|''' 9a'''
| 9b
|-
|''' 10a'''
| 10b
|--bgcolor="FAF5FF"
|''' 11a'''
| 11b
|-
|''' 12a'''
| 12b
|--bgcolor="FAF5FF"
|''' 13a'''
| 13b
|}

=References=

2017 Group Project 2

2017-10-24T08:47:52Z

Z5178275:

{{ANAT2341Project2017header}}


=Kidney=
----
The kidneys are two bean-shaped organs that play an important role in the renal system (also known as the urinary system). In the womb, the placenta is responsible for maintaining balance of water, nutrients, ion levels, etc. However, after birth, this responsibility is given to the kidneys. As such, they are vital for the everyday functions of the human body as they are the unit responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. The by-product of this process is urine, and it is excreted from the kidneys into the ureters which then deliver the urine to the urinary bladder.

Filtration is carried out in what is called the "nephron". In humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million. However, a typical kidney usually has approximately 900,000 to 1 million nephrons. Nephrons are the functional units of kidneys and are independent of each other.
<ref>https://www.ncbi.nlm.nih.gov/pubmed/21604189</ref>

Kidney development in the embryo is known as nephrogenesis and has three stages: pronephros, mesonephros and metanephros. This process typically begins in week 4 of gestation and ends in week 36. About 1 in 500 babies are born with a kidney problem due to developmental abnormalities. <ref>https://www.kidney.org/atoz/content/detectkid</ref>

Developmentally, they arise from the intermediate mesoderm.

===Anatomical Position===
[[File:kidney_position.jpeg|300px|thumb|left|'''Figure 1.''' Diagram of the position of left and right kidneys within the abdomen]]
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.

===Kidney Structure===
[[File:Kidney.jpg|400px|thumb|right|'''Figure 2.''' Cross section of the kidney displaying its inner structure]]

The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:

'''Renal capsule''' – Tough fibrous capsule

'''Perirenal fat''' – Collection of extra peritoneal fat

'''Renal fascia''' – Encloses the kidneys and the suprarenal glands

'''Pararenal fat''' – Mainly located on the posterolateral aspect of the kidney.

Their inner structure can be divided into 2 main areas: the outer '''cortex''', and the inner '''medulla'''. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as '''renal papilla'''. Each renal papilla is associated with structures known as '''minor calyx''', which collects urine from the pyramids. Several minor calyces join to form a '''major calyx''', where urine passes before it reaches the '''renal pelvis''' and into the ureter.

=Kidney development=
----
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
{| class="wikitable"
! style="background:#f4a941" | WEEK
! style="background:#f4a941" | DEVELOPMENT
|-
| 4 (early) || Pronephros begins (first stage of nephrogenesis)
|-
| 4 (late) || Mesonephros begins (second stage of nephrogenesis)
|-
| 5 || Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|-
| 6 || Ascension of kidneys from pelvis area begins
|-
| 8 || Functional kidney is formed. First nephrons are formed, a process that continues until week 36
|-
| 9 || Kidneys complete their ascension and now sit just below the adrenal glands
|-
| 10 || Kidneys now ready to perform filtration
|-
| 15 || Renal vasculature development is completed
|-
| 36 || Nephrogenesis completed. No more nephrons formed from this point on.
|-
|Postnatal || Kidney and its structures continue to mature.
|}

Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.

===Nephrogenesis===
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.

[[Image:Stages_of_nephrogenesis.png|thumb|left|'''Figure 3.''' A general overview of the three stages of nephrogenesis arising from the intermediate mesoderm. From left to right: pronephros, mesonephros, metanephros depicting the induction of the uretic bud and its first interaction with metanephric mesenchyme.]]

=====1. Pronephros=====
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.

=====2. Mesonephros=====
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.

Towards the end of week 4 of development, the nephrogenic duct starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally.

=====3. Metanephros=====
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells[1]. After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.

Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).

The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.

[1]http://www.sciencedirect.com/science/article/pii/S1534580710002078

===Nephron development===
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime <ref>Barker, N., Bartfeld, S., and Clevers, H (2010). Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell. 7: 656–670 </ref>. Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.

In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system <ref>Cebrián C., Borodo K., Charles N., Herzlinger D. A. (2004). Morphometric index of the developing murine kidney. Dev. Dyn. 231, 601–608</ref>.

[[File:nephron_development_02.jpg|350px|thumb|right|'''Figure 4.''' Diagram displaying different stages of nephron development]]

''Stages in nephron formation:''

1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.

2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia

3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body

4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.

The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days <ref>Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., and Oliver, J.A. (1999b) Mesenchymal to epithelial conversion in ratmetanephros is induced by LIF. Cell 99, 377–386.</ref>.

WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis <ref>Kreidberg, J.A., Sariola, H., Loring, J.M., Maeda, M., Pelletier, J., Housman, D., and Jaenisch, R. (1993). WT-1 is required for early kidney development. Cell 74, 679–691</ref>.

===Ascension===
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
[[File:Kidney_ascent.jpg||400px|thumb|left|centre|'''Figure 5.''' Kidney ascent. A) Week 5 B) Week 6 C) Week 7 D) Week 8. Ascension and rotation of the kidneys is therefore completed by week 9]]

===Genes Expressed===

Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.

The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.

===Blood Supply===
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart. A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction, that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, '''dialysis''' or '''kidney transplant''' is needed to filter metabolic wastes from blood.

====Angiogenesis and vasculogenesis====
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of '''Vascular Endothelial Growth Factor (VEGF)''' and its '''receptors (VEGF-R)''' during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders.

====Glomerulus====
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through '''fenestrae''', which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for '''ultrafiltration''' within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the '''renal corpuscle'''. The '''glomerular filtration rate''' is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function.

====Juxtaglomerular apparatus====
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely '''macula densa''', '''juxtaglomerular cells''' and '''extraglomerular mesangial'''.

*'''Macula densa''': The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop.

*'''Juxtaglomerular cells''': Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to '''(1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases''', '''(2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine''' and '''(3) a decrease in renal perfusion pressure'''. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.

*'''Extraglomerular mesangial''': The specific function of extraglomerular mesangial is not well understood.

====Renin-angiotensin system====
A decrease in plasma sodium level leads to the '''conversion of prorenin into renin''' by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme '''converts angiotensin I into angiotensin II'''. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.

=Developmental abnormalities=
----
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.

An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue <ref>Balbi APC, Marin ECS, Francescato HDC, Costa RS, Coimbra TM. MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. Pediatr Nephrol. 2008;23:1433–1444. doi: 10.1007/s00467-008-0830-1.</ref> <ref>Lamouille S, Jian XJ, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;3:178–196. doi: 10.1038/nrm3758. </ref> as well as a decrease of the proximal tubule cubulin receptor <ref>Lima WR, et al. ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells. J Am Soc Nephrol. 2010;3:478–88. doi: 10.1681/ASN.2009070698</ref> have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. <ref>Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. J Clin Invest. 6:1420–1428. doi: 10.1172/JCI39104</ref>

Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.

Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. <ref>Chen Y, et al (2004) Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol. 5:1232–43. doi: 10.1097/01.ASN.0000123690.75029.3F </ref>

Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism <ref>Holick MF (2013). Vitamin D, sunlight and cancer connection. Ant. Canc. Ag Med. Chem. 13:70–82. doi: 10.2174/187152013804487308</ref><ref>DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689–96</ref>, recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. <ref>Li YC, et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 2002;2:229–238. doi: 10.1172/JCI0215219</ref>

Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. '''Renal vascular anomalies''' are defects involving renal arteries and renal veins while '''fusion anomalies''' results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.

''Common congenital kidney defects include:''

* Renal agenesis (absence of one or both kidneys)

* Multiple ureters (more than one ureter draining a kidney)

* Hypoplastic kidneys (underdevelopment of the kidneys)

* Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)

* Wilms tumours (kidney cancer)

* Patterning defects

[[File:Horseshoe_kidney_01.jpg|300px|thumb|left|'''Figure 6.''' Pathology specimen showing a lobulated, fused and horseshoe kidney]]

===Horseshoe kidney===

*Common congenital abnormality of the kidneys.

* The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.

* It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery <ref>Moore KL: Clinically Oriented Anatomy, ed 3. Baltimore, Williams & Wilkins, 1992, p 223</ref>. The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.

* It shows a wide variation of arterial blood supply. <ref>Yoshinaga K, Kodama K, Tanii İ, Toshimori K: Morphological study of a horseshoe kid- ney with special reference to the vascular system. Anat Sci Int 2002;77:134–139</ref>

* During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.

* The ureters pass in front of the zone of fusion of the kidneys.

* Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.

* Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.

[[File:Wilms_tumor.jpg|300px|thumb|right|'''Figure 7.''' Pathology specimen showing kidney with Wilms' Tumour also know as nephroblastoma]]

===Wilms' tumour===

* Most common intraabdominal cancer in children <ref>Davidoff, A. M. (2012). Wilms Tumor. Advances in Pediatrics, 59(1), 247–267. http://doi.org/10.1016/j.yapd.2012.04.001</ref>; 9 out of 10 kidney cancers in children are Wilms' tumours.

* Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.

* Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour. <ref>Call K. M. et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60, 509–20 (1990)</ref> Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.

* A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.

===Renal agenesis===

[[File:Renal_agenesis_02.jpg|300px|thumb|left|'''Figure 8.''' 3D scan displays right renal genesis with the presence of a normal keft kidney and absence of right kidney in renal fossa]]

* Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.

* This defect usually occurs around 5 weeks of embryonic life. <ref>Paolo Volpe, Valentina De Robertis, Nicola Volpe Unilateral renal agenesis, Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, www.VISUOG.org, 30th of March, 2013</ref>

* It can occur in two forms: bilateral or or unilateral renal agenesis.

* Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. <ref>Kerecuk L, Schreuder MF, Woolf AS. Renal tract malformations: perspectives for nephrologists, Nat Clin Pract Nephrol , 2008, vol. 4 (pg. 312-325)</ref>

* Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. <ref>Dursun H, Bayazit AK, Buyukcelik M, et al. . Associated anomalies in children with congenital solitary functioning kidney, Pediatr Surg Int , 2005, vol. 21 (pg. 456-459)</ref>.

* It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.

=Current Research=
----
==Can kidney disease be associated with nephron number?==
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.

https://www.ncbi.nlm.nih.gov/pubmed/16014104

https://www.ncbi.nlm.nih.gov/pubmed/16774009

https://www.ncbi.nlm.nih.gov/pubmed/21604189

https://www.ncbi.nlm.nih.gov/pubmed/19615565

https://www.ncbi.nlm.nih.gov/pubmed/28818273
[[User:Z5017644|Z5017644]] ([[User talk:Z5017644|talk]]) 16:50, 31 August 2017 (AEST)

=Questions for the future=
----
==Kidney stem cells==
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro.

=General info on the renal system=
----
The renal system consists of the '''kidneys, ureters, bladder and urethra'''. The four organs function collaboratively in the '''production, storage and excretion of urine''', in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.

==Ureters==
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters '''carry urine from the renal pelvis of the kidneys to the urinary bladder'''. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in '''cystitis''', which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.

==Bladder==
The urinary bladder '''stores urine''' before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via '''micturition''', which involves both voluntary and involuntary muscles. '''Incontinence''' refers to a lack of voluntary control over micturition.

==Urethra==
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.

=Glossary of terms=
----
{| class="pretty table"
|-bgcolor = "DDCEF2"
|'''Term'''
|'''Definition'''
|-bgcolor="FAF5FF"
| ''' Angiogenesis'''
| The formation of new blood vessels from blood vessels that are pre-existing.
|-
|''' Fascia'''
| A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.
|-bgcolor="FAF5FF"
|''' Metanephric blastema'''
| An embryological structure that develops into a kidney.
|-
|''' Pharyngeal arch'''
| Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.
|--bgcolor="FAF5FF"
|''' Vasculogenesis'''
| The formation of new blood vessels via de novo endothelial cell production.
|-
|''' 6a'''
| 6b
|--bgcolor="FAF5FF"
|''' 7a'''
| 7b
|-
|''' 8a'''
| 8b
|--bgcolor="FAF5FF"
|''' 9a'''
| 9b
|-
|''' 10a'''
| 10b
|--bgcolor="FAF5FF"
|''' 11a'''
| 11b
|-
|''' 12a'''
| 12b
|--bgcolor="FAF5FF"
|''' 13a'''
| 13b
|}

=References=

User:Z5178275

2017-10-12T00:38:46Z

Z5178275:

{{ANAT2341ProjectGroup2017table}}

== Peer reviews ==

'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

'''Peer review project 3:'''

Some general comments to the project:
*The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project.
* Overall, I think the project was good. It was well written, easy to understand as a student, the sections correlated well and the context was good. I especially liked the signalling section, even though some context is missing. I think the idea of adding a treatment part to project is a good but I could not find it in the project. As mentioned some context is missing, which is the notch pathway, sonic hedgehog and retinoic acid sections.
* The project has a good introduction. You have a clear idea of what you are about to read, which is nice.
* The layout could be a lot better, I think the picture location could be adjusted. In the developmental origin part, the pictures make the section look very confusing. Some of the subheadings, like the abnormal development is pushed to side by the pictures, so when you scroll down the project you miss it.
* In general, the pictures miss their caption, sources and number. Therefore, you do not know which picture there is referred to when you are reading the project. I miss some more pictures in the developmental sections. Some of the home made drawing is not very descriptive
* In the developmental origin section I think the last sentence is very long. You get so much information in one sentence that you sometimes forget what you just read.
* The timeline is easy to read and understand. Could contain some key discoveries.
* Thought the glossary of terms is a nice addition to the project.
* Overall the referencing is good, but in some sections like primary heart field and heart tube formation, the referencing is missing. In some sections the articles/or links are at the bottom of the section, which makes it a little confusing.
* I don’t feel like the primary heart field and heart tube formation correlates very well with the secondary heart field and cardiac looping section. When I start reading the latter I feel like I am starting on something completely new instead of continuing reading on the heart developing. I get the feeling I am reading two different persons work, and some work should be put into these sections to make it feel more fluent.
* An idea for your project could be that you add a short anatomy section after the introduction, so the reader gets a picture and an overview of how the heart is structured. Then it is easier to understand the developing of the heart when you know how the heart is going to end up looking like.

'''Peer review project 4:'''
* The project does not feel like it is finished. A lot of work still needs to be done, and some of the subheadings like retina, cornea, eyelids, lacrimal glands etc is still empty.
* I did not find any sections describing signalling, research or future questions and animal models. I miss some more research content and a research angle to the project.
* The few parts of the development of the eye components which has been written was good. It was easy to understand and had good referencing.
* In general, the project could use more pictures to support the text.
* The anatomy part of the project was good. The drawing made it easier to understand, even though the picture captions and numbers are missing. I did not have any difficulties understanding it and they wrote it in a very clear way.
* I liked the overview of the eye development, it made it clear what is happening when, which cells comes from which germ layer and the Carnegie stage is a nice adding, even though it is not finished.
* The abnormal development section is far from finished. I think it is an important part of the project and it would improve the project if the anomalies where describe more in depth and not in a table.
* The glossary section was empty as well.

'''Peer review project 5'''

* The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project. But when you read the developmental origin section it does not say which germ layer it comes from. That is written in another section which I find confusing.
* Good idea drawing your own pictures, but because it is done with a pencil it is difficult to see what’s written on the picture.
* I like the anatomy introduction to the lungs – but I don’t see how the histology part is relevant to the project
* The abnormal development section was well-written and seemed like the group had done their research
* The current research section is still empty
* I liked the development timeline with the historical discoveries. But I think the development is the key stone of the project and therefore it would be nice if it had is own section instead of being the table. But the context itself was good
* I think the conducting system section is good and I like how you referred to the signalling processes which is also well described.
* Some sections still need referencing
* I liked that you included videos in your project

'''Peer review project 6:'''

* Overall the project was good and had both a abnormalities, animal model, timeline, signalling and development origin section. It does not have a current research and question for the future section.
* I like the timeline. It was nice and easy to read and gave a good overview over the developmental process. I like the use of embryonic pictures. Maybe instead of having a key historical discoveries section it could be integrated in the timeline?
* Good selection of pictures and the picture have caption. But the caption does not following the protocol.
* The abnormalities could have more context to it.
* I think it would improve the project if the timeline where before the developing process because then you read the table, get an idea about what is going to happen and then you can read the steps in detail. The developing process section could use some more breaks and pictures to make it look a little less dense.
* In general, good referencing but some sections like purkinje/pyramidal cells miss their reference.
* The anatomy section was good and informative

Here is the [[Student Page]] demonstration page I showed in the Practical class.

Use this page to practice editing and don't forget to add a topic to the [[2017 Group Project 2]] page.

[[File:Chicken embryo E-cad and P-cad gastrulation.png|500px]]

Chicken embryo E-cadherin and P-cadherin in gastrulation<ref><pubmed>27097030</pubmed></ref>

 
{{2017ANAT2341 footer}}

Talk:2017 Group Project 6

2017-10-12T00:38:22Z

Z5178275:

{{ANAT2341Project2017discussion}}



=Project Starting Places=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 6 below are some starting places.
=What to improve from peer reviews=
z5076158 Tick off once this has been adjusted:
*Future Research Questions heading
*Split up adult and embryo anatomy under heading “basic anatomy”
*Break down development – use dot points for types on grey matter etc, first paragraph is a big block of text – subsection it
*Key historical discoveries – add images
*Current research heading
*Change the blue title
*Basic anatomy – talks about development, move it to that heading
*Cerebellum development table takes up a lot of space
*Pictures in second trimester section of table
*Neural development heading moved to cerebellum development
*Caption photos placed together for abnormalities section – make photos look neater
*Move timeline to before the info about development
*Key historical discoveries – use a table with 2 columns – name of discoverer and brief description
*Improve on cell signaling in cerebellar development (bit length), key discoveries and animal models, make them more engaging with photos, videos etc.
*merge the introductions
*add images to microanat
*don’t centre text for cerebral nuclei table
*place info about primary and secondary vesicles above their images
*introduction repeated the word ‘hence’ too much
*look over reference list – some were just links
*references for weeks 3-6 on developmental timeline
*repeated references
*student drawn diagrams!
*link other wiki page entries
*utilize videos

{{Neural Links 2}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebellum+Development ''Cerebellum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebellum+Development ''Cerebellum Development'']

Cerebellum: links between development, developmental disorders and motor learning; [http://journal.frontiersin.org/article/10.3389/fnana.2012.00001/full]

Cellular commitment in the developing cerebellum [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290586/]

Recent papers

<pubmed limit=5>Cerebellum+Development</pubmed>

==Neural Development==
(z5114433)
will fix referencing stuff later #ceebsrn

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the folding of the neural tubes to form the cranial and caudal region of the embryo (''https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'') . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

=z5114433=
structure
time course
functional developing
what cells appear when

glial cells development

4th ventricle

Genes in abnormalities

pathway of development of cere cells
start of as neuroblast

=z5018156=
Things to remember:

Coordinates muscular activities - walking, crawling, writing

Embryo doesnt need the musuclar activities

Prenatal - neurons develop to carry out those activities later on

Postnatal - wiring up

Neural tube

Comes from pontine flexure - 4th ventricle -- the cerebellum develops into this space

Lamination of the cerebellum

https://www.ncbi.nlm.nih.gov/pubmed/19732611

https://www.ncbi.nlm.nih.gov/pubmed/21380713

Development: z5018156 - https://www.ncbi.nlm.nih.gov/pubmed/21295689

=Z5076158=
==Week 7 Work==
What I could add: Paramotal cells, molecular layer, what cerebellum connects to, how they are remodeled postnatally Kahals research
https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-150-the-brainstem-metencephalon-fourth-vesicle-the-cerebellum - good reference
LARSONS HUMAN EMBRYOLOGY TEXTBOOK
The metencephalon gives rise to the pons and the cerebellum, the adjacent rhombic lips also contribute to the development of cerebellum. The pons functions to relay signals that link both the spinal cord and cerebral cortex with the cerebellum and the cerebellum is a centre for postural and balance control. Pontine nuclei relay information from cerebrum to the cerebellum.
The cerebellum is first recognized as a pair of thickened cerebellar plates or cerebellar primordia.
Adjacent rhombic lips gives rise to Cerebellar granule cells
Major portion of the cerebellum consists of a narrow median swelling called the vermis and this grows faster than the flocculonodular which were the primitive part of the cerebellum and therefore becomes the dominant portion of the mature cerebellum.
Folding:
Primary fissure deepens by end of third month and divides vermis and hemispheres into a cranial anterior lobe and caudal middle lobe. Lobes divide further into lobules due to development of transverse fissures. This fissure formation and foliation continues throughout embryonic, fetal and postnatal life and this is done to increase the surface area of the cerebellar cortex.
2 types of grey matter present:
- Internal deep cerebellar nucler
- External cerebellar cortex
4 deep nuclei and all output of the cerebellar cortex is relayed through these nuclei.
These nuclei and cortex are produced by a process called neurogenesis and neuronal migration
1. Dentate
2. Globose
3. Emboliform
4. Fastigular

4th month – germinal layers undergo cell division and this produces populations of cerebellar neurons.
• Ventricular layer – purkinje cells, golgi cells, basket cells, stellate cells
• Granule cells remaining from the cerebellar cortex (these arise from external germinal layer)
• External germinal layer – primitive nuclear neurons these migrate to form deep cerebellar nuclei
==Week 8 Work==
PAPER 1995
Cerebellum – about:
It consists of 3 layers with 2 principal classes of neurons
Granule cells studies of naturally occurring mutations and targeted gene disruption that block discrete steps in development of this region
Development of anterior portion of neural tube involves the formation of 3 brain vesicles:
1. Prosencephalon
2. Mesencephalon
3. Rhombencephalon
Division of rhombencephalon into metencephalic vesicles and myelincephalic vesicles (this forms in day 9)
Failure of neural tube closure creates gap along the dorsal aspect of the neural tube, which bows into a mouth-like structure as the tube bends to establish the pontine flexure.
Further deepening this newly formed pontine flexure, bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brainstem) fold underneath developing the cerebellum plate.

Cells fated for cerebellum are derived from both the mesencephalon and metencephalic vesicles (rhombencephalon). Neuroepithelium of the mesencephalon generated majority of the cells in the cerebellar cortex: V-like area of mediodorsal aspect of the anlarge arose from a caudal movement of cells from the mesencephalon.

PAPER 2014
Cerebellum has a very basic structure:
• Monolayer of inhibitory purkinje cells sandwiched between a dense layer of excitatory granule cells
• Subpiled molecular layer of granular cell axons and purkinje cell dendritic fibres
Granule cells receives inputs from outside the cerebellum and project to the purkinje cells, the majority of which then project to a variety of cerebellar nuclei in the white matter.
The area designated for the cerebellum to reside (anlage) during development was located between hindbrain and midbrain. Regulation of patterning in this early stage (E9) of development shows to be particularly important for development of the uniquely mammalian midline expanded region of the cerebellum, “vermis”.

Specific cell types are allocated along the dorsoventral axis. For glutamatergic cells of cerebellum, remarkably prolonged establishment and an important dynamic process that takes place at most dorsal interface between neural and non-neural roof plate tissue, the rhombic lip. This phase generates the basic dichotomy between GABAergic and glutamatergic cell types that underlies the conserved Purkinje-Granule cell circuit.
Cell type allocation proceeds a third, distinct temporal phase of development that extends into early prenatal (up to 2 years). In this phase, the principal derivative of the rhombic lip, the granule cell precursor, accumulates over the surface of the cerebellum and undergoes further rounds of symmetric division in a process of transit amplification that exponentially expands its numbers.
The anlage of the cerebellum is a product of mechanisms of segmentation that establish iterated rhombomeric subdivision within the hindbrain just after neural tube closure.
All cells of the cerebellum arise from dorsal rhomomere, a region definitively classified by absence of the expression of Otx and Hox genes. Majority of cerebellum arises from metencephalic (rostral) hindbrain.

==Peer Review to other groups==
===Group 1===
The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

===Group 2===
I believe the headings chosen cover a sufficient amount of points you need in order to describe kidney development!
Referencing needs to be changed, its easy to use the code <ref> <pubmed>INSERT PUB MED ID</pubmed> </ref> and that automatically makes a reference for you!
When describing position, explain what retroperitoneal means, its not commonly known and also Thoracic 12 (T12) so people know what T12 refers too.
For images, you need to find the copyright information and reference them properly, Mark has step by step instructions on what needs to be included in the image description. There aren’t many references in the first section of the page, it would benefit if you included some. Under nephrogenesis, point 3, you can find the articles pubmed ID and add the reference in that way instead of manually doing it.
For developmental abnormalities, I feel like this could be explained better, it gets technical straight away and this can become quite confusing.
Current research and questions need to be worked on but I’m sure that’s whats intended.
Overall I think the content on this page is very relevant to kidney development and it was interesting to read. The two major things you should fix are image copyright and references and intext referencing.

===Group 3===
Introduction is very good and explains a lot. Under the heading “Primary heart field and heart tube formation” – the reference at the bottom should be removed.
Secondary heart field and cardiac looping: First sentence doesn’t really make sense, maybe switch it up a bit.
Under current research and findings you have labelled a figure figure 1, when it is not the first figure in your wiki page, seems a little confusing. Images also don’t have appriopriate copyright info, description and referencing. Also figure 2 is placed right in the middle of the sentence, maybe put it to the right so it doesn’t interrupt reading.
Information could be formatted better under the heading atrial septal defect! Maybe some subheadings for the different defects? Same goes with the ventricular septal defect, its easier to read when things are broken up. Glossary is very good!

All the information written on your page is very well written and easily understood.
Images could be labelled better, add a figure to each of them as when you are referring to figure 1 and 2 in your writing, the images aren’t labelled so its hard to tell what image you are referring to.
With references, I don’t like how there is a bunch at the end of some headings? Could be because you still need to read them but looks messy.
There is an overwhelming amount of information, so good job on doing so much research but it was quite tedious to read, not sure if this much information is needed? But it is very hard to fault your wiki page so this might be a bit picky.

===Group 4===
Reading through this page was very interesting and informative however I have a few points that could be adjusted to improve on your page. When inserting an image, adding a figure and brief description on the images would be useful. The timeline is good but there is no reference so it definitely needs one. When reading through all the other tables, references need to be used more as it isn't that easy to figure out what articles you have used to get your information. More work needs to be done to fill the headings under development of eye components and if more images were added it would be useful. Abnormalities could have a bit more of an explanation written as well. Your wiki page is looking good, I would suggest a heading on animal models would provide some good information and fit well with your page! I also haven’t read anything that tells us about signaling, this should have its own heading and should be explained quite well as it is an important part of development. With your figures, it would be nice if you referred to them throughout your text more, and integrated them with the headings. Although this page is a work in progress, the information written is useful and easy to understand.

===Group 5===
This wiki page is very informative and good to read! When reading I noticed that the images don’t have a figure number, although this isn’t necessary, it can make it easy to refer to figures in text and therefore explain them better. For the heading lung histology, you can add proper dot points by adding an asterix before the information, this will make your page present better. Both headings future questions and current research need to be finished as they are incomplete. Using self drawn pictures makes your page easy to follow and understand, this is a great feature of your page. Copyright information is added well for the most part, however I found some images under the heading “Developmental signaling processes” which didn’t have any copyright information or an appropriate description, also make sure the student template is added at the end of every image description. I particularly enjoyed the timeline, it is very well written and is easy to understand. Good job on the project thus far.

=z5113034=
Vasculature of cerebellum originates from vertebral arteries and the arteries that arise from it.

Metencephalon; temporary structure that differentiates into pons and cerebellum ventrally and dorsally respectively.

Current Research

Key discoveries during research of cerebellar development

=Topic Selection=
Hi group! I am personally interested in the development of the heart! Also, are you guys happy to exchange details after the lab tomorrow? - z5018156

Hi! Im happy to share details! And yeah heart would be interesting, but I was also thinking maybe the ear? that could be cool

Hey, yeah I was thinking the heart- I did a course on it last semester, but i also feel its quite generic and the other groups would do something similar. Shall we wait until the end of prac and find each other? Call out number 6 LMAO (z5114433)

Hey all! I'm pretty open about topics but I was leaning towards the eye? Unless that's too close to optom, (and it might be a popular subject too?) I'm fine with anything. Let's find each other after prac! -z5113034

The ear sounds good as well as the eye, theres also the lungs as well! We can just make a list and then decide as a group! - z5018156

=Peer Review=
This page is very informative, well set-out, and easy to follow and read. The information is well-referenced and the images have a description, the correct Copyright, however some lack the appropriate Student Image template. The "Key Historical Discoveries" and "Cell Signaling in Cerebellar Development" sections could be broken up with relevant images. Other images I find are too large and could be made smaller. The smaller amount of information above the "Introduction" would flow better if it was all included as one introductory paragraph. The images in the "Abnormalities" section could include a small description directly under them to describe the image and make it more uniform with the other images on the pages. Reference list is extensive and done very well. The page could be improved by including a "Future Research Questions" section. Overall very hard to fault!

---

The information is really well written and informative. The use of images is really good, especially with the description and when they have been included in the table. The section on the Historical Discoveries is a really interesting part and adds a good amount of background information to the cerebellum. Maybe add a table for the glossary section part that just relates to the terms relating to the cerebellum. Make sure that all references are referenced properly, not just the addition of the links. Overall, a really good wiki and the information is understandable and very well done.
---

This page was easy to follow and had good flow, with relevant headings and subheadings relating to the development of the cerebellum. Basic anatomy of the cerebellum contained a good amount of information, which provided relevant background knowledge before jumping into the development. Images were nicely chosen and was very relevant to the content, and they were also cited properly. There were some sections under Anatomy of the cerebellum that were related to the development, so it would be better to move it into the "Development" section to further improve flow. The table of "Cerebellum Developmental Weeks" was very clever especially with the images used. There is a vast amount of references used, and they were done properly. A "Further questions" section is needed to address any research gaps as well as explore more information on the Cerebellum. So far, well done!

---

There is a good introduction into the cerebellum which is also connected to the page and what the page will explore. The “basic anatomy” subheading is nice and succinct with minimal text and clear diagrams that clearly represent the anatomy of the cerebellum. The “Vasculature” subheading also provides a good overview with a simple diagram to complement. The only thing I find a bit odd about all the subheadings under “basic anatomy” is that I feel as though we go from the adult human anatomy of the cerebellum into embryological anatomy of the cerebellum. I think it might serve you better to split these up or just rearrange/rename your subheadings a bit. The reason for this is because the cerebellum is quite complex so I think it would help to absorb the information.
The “cerebellum development” is a good and descriptive subheading with a good use of diagrams. Since there is quite a big chunk of text, it would probably be better if you broke it down where you could. So, for example, where you say: “there are two types of grey matter in the cerebellum…” you could easily use dot points. It just helps with readability.
The “cellular migration” subheading is very good and the diagram you found is a great representation of it. I like that you added images to complement each week of development in your first trimester timeline. If you can do the same for your second trimester timeline that would be great. Your “key historical discoveries” subheading could use some images (even if it is of the people who made the discoveries). You chose a good number of abnormalities to explore in that last section. You might want to add another section for “future questions” just to hint at what more we need to learn about cerebellum development. You have a solid, long list of references.

---

Really good project page. The page goes through almost everything required for the project. You need a section about Further Questions and Current Research. The project is really well written and easy to understand. There is a good introduction giving the reader an idea of what to expect from the project page and good use of pictures giving a basic understanding of the anatomy of the cerebellum. There is a lot of use of figures and tables, which makes it easier for the reader to understand the subject. Most of the figures have a figure number and text, this also makes it easier to get a quick view of what the text refers to. The layout of the page is also comfortable to go through, but I do think the title Cerebellum in blue is a bit disturbing. There is good use of references.

*It seems like you have mixed the context in '''Basic Anatomy of the Cerebellum section''' and the '''Cerebellum Development'''. During the 'Anatomy section, you start describing the developmental origin, which I think would fit better in the Developmental section.
*The first section in the '''Cerebellum Development''' has a lot of text. Maybe you can make some subsections to split of the text and makes it more comfortable to read.
*The '''Cerebellum Developmental weeks table''' is really good and has good use of pictures. But the format makes it really big. Maybe you can do this part in a different way, so it does not take that much space. For the table about the second trimester, it would be a good support for the reader to add pictures to this table too – like the first-trimester table.
*The '''Key Historical Discoveries''' has a lot of text. Maybe you can add some pictures or change the layout a bit.

---

Very efficient page in its structure and attention to detail throughout the text. Subheadings are easy to follow and did not cause any confusion. The use of diagrams and images are relevant and accompany the text well and are referred to as figures which elevated the efficiency, however, inconsistencies in labelling the images are evident with many images lacking the figure number such as “diagram of a 2 day old…”. This would ease the process of referring to images throughout the writing and improve the reading experience. There is no section on current research or further questioning which is a shame as it is an interesting aspect of reading these pages and I feel it would add an up to date relevance to the overall page. Expansion on the abnormalities mentioned under the subheading is required as only a few are mentioned and not discussed. Some of the technical terms were difficult to follow so definitely a glossary would fix this. Referencing seems to be quite consistent throughout for the most part, however some areas are lacking acknowledgement to resources. Overall, an informative page which demonstrates a thorough understanding of the cerebellum.

---

Overall, this team's wikipage was really informative. They were detailed yet not too much information was given. There was a good balance with text and pictures. The pictures chosen were all of good quality as well with appropriate description, referencing and copyright information provided. The introduction was a very good brief of the entire page and explained what was to be expected. In the basic anatomy of the cerebellum, the subheadings were really well-defined. However, maybe neural development should be shifted to the developmental section instead. This section was well referenced. I like the use of the table to describe the cerebellum developmental weeks. The images used were really helpful in visualizing what was happening in those weeks. In the abnormalities section, it was short and concise with good picture. Maybe the caption of the photos could be placed together with the photo such as those in the table. This could make the photos look neater. Overall I find that this wikipage was well done, it had a good amount of text and photos and the references were all properly included.

---

Overall, I think this project page is really good and well done to the team. I think the headings and subheadings flow easily and there is a good arrangement of information. There is a good amount of referencing and the images have copyright statements and brief descriptions. For the “Neural Development” subsection, instead of placing it under the anatomy of the cerebellum, I think you should move it down to the development section as it has more relevance to that. I think the Cerebellum Developmental weeks should be shifted to before the description on cerebellum development. This way, the readers can have a general idea on the development and its stages before going through he description because the description is quite content heavy and if we were to read that first, its quite confusing and hard to understand. For the key historical discoveries, maybe you could use a table with two columns where one column can be the name of the discoverer and the other column could be a brief description. The abnormalities section was done well.

---

Overall this project is very extensive and appears to almost be complete. The structure and lay out is clear and easy to follow. The numerous tables and diagrams are very engaging. The material seems to be relevant, informative and well-referenced. I think the you could combine the first section into the introduction as it is confusing to have two introductory sections. Also the blue title could be larger and at the top of the page to highlight the overall topic of the project. The sections of ‘cell signaling in cerebellar development’ and ‘key historical discoveries’ and ‘animal models’ are not very engaging to read as they are just large chunks of text and perhaps images, videos or collapsible windows could be used to break them up and make them more attractive. Despite these minor suggestion, your project is extremely well done!

---

The introduction and the information above the introduction is really good, however, I think it would be better if you merged these into one as it sort of seems like two introductions and doesn't flow very nicely, even though what you're saying is really good. The basic anatomy was really good, especially with the images and the reference to them. The microanatomy information is good however would be better if you added images like you did in the anatomy. The cerebral nuclei table is good, however, I think its distracting the description in the centre, just have it normal and don't centre your text. Place the information about the primary and secondary brain vesicles above their images and then refer to the images. Some of your sections, for example, cell signalling or key historical developments, are really wordy and hard to keep a focus so maybe split them up with images, videos, or tables. The rest of the page looks really good, maybe just add some more information to the abnormalities as some are only a sentence or so. The page could also benefit from using a video or two. Referencing is good.

---

It was really good that the structure and function of the cerebellum was explained in a succinct way in the beginning. The introduction repeated the word 'hence' a few times, maybe it's better to modify it into bullet points, in a similar way when lecturers provide a slide on the lecture overview. Appropriate images were added as well as figure labeling. Copyright approval was also provided for the images and were referenced appropriately. The use of tables was also appropriate in some of the topic sections. Images were also in appropriate sizes that avoided covering the while page. The page was very detailed as well. Some sections like "Cell Signaling" was a bit lengthy, images would be nice. It was good that reputable journal articles were used for the project, proper in text citations superscripts were also done properly. However, revise the reference list because some were left as links and the list did not have a consistent reference format. But overall, the page looks almost complete.

---

This page seems to have the one of the best organizations. All the sub headings needed for the project are included and completed (minus further questions). The introduction is a nice addition as it gives a roadmap to your page. The entire Basic Anatomy is informative and sectioned nicely into the most important topics--some of the images may be a bit too large however. I like that the information for the first and second trimester is separated, instead of clumping it all together. Cerebellum development, cell signaling, and key historical discoveries have a lot of text and might need some diagrams or tables to break up the text. Also it would help to put the key historical discoveries at the beginning so that the reader knows how it led to the information we know today. The neural development section should be moved below microanatomy and before early brain vesicles since it leads into that section. The

----

This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The ‘basic anatomy of the cerebellum’ section is written well and in detail. It provides a solid introduction to the wiki page, as well as background information that assists in understanding other sections. The chosen visual aids enhance the written information, and allow the reader to visualize some of the more complex ideas.

The ‘signaling processes’ and ‘key discoveries’ sections were both well addressed, with the information being expressed clearly.

The developmental timeline provides a nice summary of cerebellum development, especially throughout the first trimester. The accompanying images are both relevant and useful in understanding the text.

Overall, the wiki page is structured well, with the chosen sub headings making the page easy to navigate.
| The wiki page lacks some important areas of information, including:
*‘Future questions’ regarding development of the cerebellum
*‘Current research’ in relevant fields
*A glossary of terms

Some sections could also be improved. The ‘animal models’ section has been addressed minimally, with only one example being provided. Try to include several more examples of animal models. In addition, the ‘abnormalities’ section lacks detail for some of the examples (see ‘rhombencephalosynapsis’).

Some areas of the wiki page would benefit from visual aids, such as the ‘animal models’ and ‘signaling processes’ sections.
|-
|2. Content is correctly cited and referenced
|Most areas of the wiki page contain some degree of referencing. ‘Cell signaling in Cerebellar development’ was the most well-referenced section.
The reference list is extensive and is mostly correct. The majority of the sources in the reference list are peer-reviewed primary research articles.

Most of the images on the page have been referenced correctly (see all images in the ‘abnormalities’ section).
|Referencing throughout the wiki page is inconsistent. Some areas contain minimal in-text citations (see ‘cerebellum development’) and other sections lack referencing entirely (see weeks 3-6 of the developmental timeline). Remember to cite any and all text that is unoriginal in regard to idea or structure.

Some of the images on the wiki page have not been referenced correctly (see ‘lateral view of embryo central nervous system at 5 weeks’). In addition, the copyright section of figure 4 states that ‘copyright has been requested’; avoid uploading images until after the copyright request has been approved.

Some references have been repeated in the reference list (see references 47 and 48).
|-
|3. The wiki has an element of teaching at a peer level
|The information presented on the page is written at a level suitable for peers.

Many of the chosen images and tables help clarify some of the more difficult concepts discussed on the page.
|Many of the acronyms and terms used in this assignment are either poorly explained, or not explained at all. Remember to include relevant definitions in the ‘glossary’ section of the page.

The page currently lacks student-drawn diagrams; try to include some for the final submission (and remember to cite the source of inspiration).
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The wiki page addresses most of the relevant learning aims of embryology, including embryonic development, a developmental timeline, signaling processes, key discoveries, animal models and congenital abnormalities.
|There are some sections relevant to the learning aims that have not been included, such as ‘current research’ and ‘future questions’.
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Most of the content on the wiki page has been researched well, particularly the ‘basic anatomy of the cerebellum’ and ‘cerebellum development’ sections.

The reference list contains a large variety of reliable sources of information (i.e. primary research articles). This demonstrates that this topic has been well researched.
|Links to other wiki pages on the UNSW embryology wiki have not been included. Try linking some sections of the page to other wiki entries, such as ‘lecture 4 – week 3’ or ‘lecture 5 – ectoderm’.
|}
--- 
Strengths: 
• The authors of this wiki page have included a variety of topics relevant to the development of the cerebellum. Topics range from the normal anatomy of the cerebellum, abnormalities, and the normal developmental process to animal models. Thus it is evident that criteria 1 has been satisfied which is excellent! 
• A broad variety of tables and images have been utilized within this wiki page which is another excellent feature that has been included. Not only has this enhanced the presentation of the page, but the images serve as a visual aid in assisting in the explanation of certain concepts to peers (particularly those who are visual learners) (criteria 2 and 4 satisfied). For example the use of images was utilized to help simplify the explanation regarding the vesicles that development. 
• It also appears that authors have included a broad variety of references in-text to cite all information utilized. Most source utilized appear to be recent and all have been correctly cited (criteria 3). 
• The authors of this page have also explored evidence of significant research relating to basic and applied sciences that extends beyond the formal teaching activities (criteria 5) by exploring avenues including animal models and how the use of animal models have contributed to our understanding of the cerebellum. Authors of the page have also explored abnormalities of cerebellar development which was excellent 
Areas of improvement: 
• In order to improve, authors may wish to expand on different animal models utilized.
• The authors of this wiki page may also wish to utilize videos as another visual tool to aid in the presentation of content included. 
• Another area of improvement would be to cite sources that are of a more recent date, rather than citing sources from the 1970s. The reason being is that such sources may include information that is currently outdated, thus the page may be providing inaccurate information about cerebellar development. 
• Authors of the page may have also covered certain topics in greater depth. For example the heading titled “Cell signaling in cerebellar development” may have been subdivided into different types of genes and signaling factors involved in cerebellar development. Authors may then elaborate on each gene/signaling factor. This will help enhance presentation whilst also improving the readability of the information presented.

Grade: DISTINCTION

General Comments:
Most sections of this wiki page have been presented at a high standard. There are only a few areas that could do with some improvement.

---
'Basic Anatomy of the Cerebellum' has really useful and clear diagrams that support the content. However, the content was a bit brief in this section. All easy to read and follow. 'Early Brain Vesicles' has useful diagrams but needs more text to back them up. 'Cerebellum Development' is well written and referenced with appropriate diagrams and captions. 'Cerebellum Developmental Weeks' has very brief descriptions; needs to be more detailed and the pictures better explained or better captioned. 'Key Historical Discoveries' are interesting and well referenced. 'Ramon y Cajal' might need to be corrected to 'Ramon and Cajal' if reference is in Spanish.. Maybe add some pictures to this section too. 'Animal models' could use more subheadings and more examples of animals models as there is only currently one described. 'Abnormalities' has interesting pictures and examples but is a bit brief in its descriptions. Overall, interesting topic and well used pictures. Some sections still need work; Glossary and maybe add a 'Future Research' topic to the page. Also a requirement of the project is to include one hand-drawn diagram which has not yet been added.
---

'''Peer review project 6:'''

* Overall the project was good and had both a abnormalities, animal model, timeline, signalling and development origin section. It does not have a current research and question for the future section.
* I like the timeline. It was nice and easy to read and gave a good overview over the developmental process. I like the use of embryonic pictures. Maybe instead of having a key historical discoveries section it could be integrated in the timeline?
* Good selection of pictures and the picture have caption. But the caption does not following the protocol.
* The abnormalities could have more context to it.
* I think it would improve the project if the timeline where before the developing process because then you read the table, get an idea about what is going to happen and then you can read the steps in detail. The developing process section could use some more breaks and pictures to make it look a little less dense.
* In general, good referencing but some sections like purkinje/pyramidal cells miss their reference.
* The anatomy section was good and informative

User:Z5178275

2017-10-12T00:37:25Z

Z5178275:

Talk:2017 Group Project 1

2017-10-12T00:11:13Z

Z5178275:

{{ANAT2341Project2017discussion}}



=Cerebral Cortex=
==Introduction==
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:37, 23 August 2017 (AEST)

==Lobes and Function==
4 Lobes: parietal, temporal, frontal, occipital
Video Overview: [https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/nervous-system-introduction/v/cerebral-cortex "Cerebral Histology"]
[[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:32, 23 August 2017 (AEST)

==Neocortical Development==
Nature article: https://www.nature.com/nrn/journal/v9/n2/full/nrn2252.html [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

===6 Layers===
Layers I, II, III, IV, V, VI (see [http://www.ruf.rice.edu/~lngbrain/Sidhya/ "Cortical Layer Review"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Anatomy and Function==

to do:

-change from dot points

-add images

-references

-finish function information

===Cell Types===
http://www.ruf.rice.edu/~lngbrain/Sidhya/ [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:57, 23 August 2017 (AEST)

==Abnormalities==
PubMed Article: [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024757/ "Developmental Disorders"] [[User:Z5177691|Z5177691]] ([[User talk:Z5177691|talk]]) 22:41, 23 August 2017 (AEST)

=Peer Reviews=

---

This page is very well structured and sequential. It provides a very detailed explanation of development under chronological subheadings. Subpages under images are well informed, but some images lack a proper Copyright phrase and Student Image Template to indicate reproducibility. On the main page, some subheadings need to be capitalised (formatting) and student signatures need to be provided on relevant sections, rather than student numbers . The "Anatomy of the Cerebral Cortex" section is filled with dot points, and could be improved using paragraphs, images and Wiki formatting. The layout of the Abnormalities section could be improved, by changing the headings and subheadings. The images and videos on the page are all very relevant to the topic, but I don't think the screenshots from youtube are appropriate of reputable. The page could benefit from a glossary list and 'Future Research' section. However, the reference list was well constructed. Overall the the page addresses the brief very well.

---

Be careful in how the sentences are expressed for example in the introduction ‘the cerebral cortex is actually the outermost layer’; avoid using ‘actually’ in this sentence. Don’t forget to remove the student numbers from the posts. Minor grammatical errors; no use of commas in long sentences. The images do include copyright however the team has forgotten to place the Student Image Template that is required. The team should add a small description of the images that are on their webpage so readers will see immediately what the image is showing. The team could do a further questions subheading or an animal model subheading to explore more on the research of the Cerebral Cortex.

Subheadings and content that have been used show a good understanding of the topic area. The use of dot points where necessary are done well which makes the project easier to understand and read through. The use of tables to demonstrate the ‘Timeline of Corticogenesis’ is done comprehensively; maybe an image for each day that is explained should be added to show consistency (as only the last row has an image). The team has used their own diagrams which shows that the team was innovative in displaying their research. The references used are cited correctly, however, there are links at the bottom where they need to fix up and place it under references.

---

Overall, the page is has nice structuring making it relatively easy to follow. But they are missing major topics necessary including historical discoveries, developmental signalling processes, current research and animal models. The introduction was short and concise, which provided a relevant amount of background knowledge. The anatomy and functions of the cerebral cortex could be put before the development so that it ties in with the introduction. The images and videos were relevant to the topic, which aided in understanding the content. However, labelling, adding a description and citing is necessary for images and videos which has not been done. A table would be a great feature for the timeline because right now its annoying to read and has a messy, unfinished look. References need fixing.

--

The page has good structure and formatting, however there is a significant unfinished touch. Anatomy of the Cerebral Cortex heading could place all the information in a table to make it easier to read as well as images to help the viewer visualise the process. Maybe remove the student numbers because they are unnecessary and make the page look not as professional. figures and tables need to be labelled as well as referencing and copyright claims. The diagram under the statement "Migration and division of all six layers of the cortex is completed during the third trimester. Each layer has distinct synaptic connections and cell types that contribute to the specific functions of the cortex." needs to be further explained because I had a hard time understanding the image and what each section meant. The video is a nice touch to help understand the function and placement of the cerebral cortex. Developmental abnormalities was well written, easy to understand and flowed nicely.

--

Well-structured and provides a vast amount of background information on the functions and structure of the cortex before delving into the details of development. However, the anatomy of the cerebral cortex and the layers are difficult to understand due to heavy use of dot points – perhaps images would be of good use in this section. There is consistently limited evidence of in-text references or citations throughout the information (rather than at the beginning of some of the sections) which makes it harder to link or follow where information was gathered. Headings are concise and easy to follow however the “other info to add” subheading under “Anatomy of the Cerebral Cortex” needs to be reworded for efficiency. Under the subheading “A) Disorders due to …” the disorders are inconsistently numbered – a 2 needs to be placed with “Hemimegalencephaly” as well as 8 with Schizencephaly. Functions of the cerebral cortex is hard to follow as dot points are used with lacking descriptions or expansion. Perhaps further discussing the actions of each functional area would provide more sufficient information in this part.

--

The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

---

The introduction was a good opening to the Cortex page as it gives a brief overview and understanding of the cortex generally. The next subheading, “Early development of the Brain”, provides of a simple and clear explanation of the early development process however images would be a great addition to help visualise the text. Try having a look at some images that were shown to us in previous lectures on the brain development where it showed the neural plate, neuroectoderm and subsequent developments.
The next subheading, “Development of Cerebral Cortex”, would probably do better to be called “Later Development of Cerebral Cortex” as it would be a seamless flow from the previous subheading of “Early development…”. It was good that a labelled image was used and information was added for explanation. It helped orient me as I was going on to read about the timeline of corticogenesis. The timeline was detailed and the use of bold helped highlight key terms. However, I would suggest making another column for images on each day. Visual reinforcement just makes the information easier to absorb and make more sense.
The subheading, “Anatomy of the Cerebral Cortex”, is clearly in the editing process. I would just once again definitely recommend the use of images in this section, both hand-drawn diagrams and labelled images from the internet. I thought the use of a video was a clever way to cover the cerebral cortex functions. A bit of general text that briefly covers the functions of the main parts would be a good addition in this section, as a segue into the video.
The “Abnormalities” subheading was a good balance of text and images. It was easier to read because it was split into categories. I would only suggest that you mention at the beginning of the section that abnormalities associated with the cerebral cortex development can be divided into the following categories… I can see the references were placed at the beginning of the section and I’m assuming that is temporary. It is better if they are dispersed within the text where appropriate. There are a good bunch of references but you could probably aim for 25-30 for this page.

---

This page needs some more information about current research, signaling processes, future questions and references to animal models. It would also be good with a table or quick overview of developmental origin. There has been a good use of pictures and tables. The setup of the section about abnormalities is really good. This page needs to use more references during the sections and not only at the start of a section. A glossary list would also be good for the reader to understand the page.

*'''Introduction''': Gives a quick knowledge of the cerebral cortex. A picture would be good to support this introduction and maybe a bit more description of the different terms. This section also needs references.
*'''Early Development:''' Good setup with bulleting. I find some of the context a bit confusing to read - especially these two sentences "From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five" and "During the fifth week, the embryonic brain undergoes rapid growth folding the neural tube and consequently resulting in three brain flexures" Maybe you can rephrase this.
*'''Development of Cerebral Cortex:''' Good section! Good overview.
*'''Timeline of Corticogenesis:''' Please give a short introduction of what Corticogenesis and Neurogenesis means. Good picture supporting the E50-55, maybe you can put this picture already in the section called "Key developmental zones in the human cortex" since this is the first time we get introduced to the different zones and plates and it would give a better basic knowledge before getting into Corticogenesis.
*'''Anatomy and Function of the Cerebral Cortex''': These two sections should maybe be earlier on the project page together with the introduction since it's a basic understanding of the Cerebral Cortex. Both sections look a bit messy, try to work on making it more simple and easier to read - it kind of looks like personal notes and not a proper information site :-) These sections also need some references. The video in this section gives a good understanding. Good idea putting a video on the page.
*'''Abnormalities associated with Cerebral Cortex Development:''' This section is really good. Great overview of the different scenarios and a lot of pictures to support the reading. Instead of mentioning all the references in the start of the section, you should add the specific reference used for each subsection, this will make it easier for the reader to look up references for specific sections.

---

In the introduction section, it was not referenced where the information facts are from. This section should introduce a brief information on the topic, what you are going to discuss on the whole wiki page, introduce current researches and animal models to support the new findings and understandings. Also, don't use "actually" in the sentence.
On the page, It is better to write in full sentences instead of dot points as I've seen a lot of them and include any of scientific words in the glossary section at the end of the page. Where you've inserted picture, it will be clearer to also include it within the text in brackets for example (Figure 1).
Any figures or pictures on this page needs references as well.
In the abnormality section, it is well written with supporting pictures, but in my opinion, it is easier to read if the the figures/pictures are on the same side and texts on the other side instead of alternating. This section was very thoroughly referenced too. I think a small paragraph under the heading introducing the different type of disorders before going into greater details.
Don't focus too much on the anatomy as I can see this section is not finished nor written in paragraph and no pictures or figures, would be better to swap anatomy with some other embryology discussion for example, signalling processes.
Touch on current researches, animal model if any and future questions as they were not seen on the page. Also include a glossary table. References section is looking good but more is needed.

----
Overall, a really informative and well-written wiki. The information was well presented and was understandable. The abnormalities section of the wiki, was particularly well done, as it was a good idea to group each abnormality with the disruption of the main event that lead to the abnormality, as it informs the reader that different abnormalities arise from a disruption of different processes that occur in the development of the cerebral cortex. The diagrams and pictures were useful as it functions as a reference point.

Overall, the layout was good, however maybe use more of a dot-point layout in the Anatomy section and maybe add some diagrams of pictures to enhance the information given. Also the sub-title "what is it?" is probably not needed as the introduction itself suggests that you will be describing what the cerebral cortex is and what is does. The Functions of Cerebral cortex may also need a bit more text as the video should just be a supplement rather than the main source for information in that section. Overall, well done as it was an informative and well written wiki.

---

Overall I find the information provided to be concise and easy to understand. The introduction was great in giving us a brief overview of page. The layout of the early development of the brain and the development of the cerebral cortex was really nice. I like the use of bullet points as this makes it easier to read. Also good amount of referencing is seen in this area. The use of the table is also a nice touch to the page and I like the picture used for E50-55. However, it could help to have another column with pictures for each row. That would help with the understanding of the text. For the anatomy of the cerebral cortex, it seems a little messy and hard to read as it is too point form. Perhaps these could be phrased into proper sentences with certain parts placed into bullet points to make it easier to read. Also, with the anatomy, pictures would be very helpful to aid in the explanation. For the functions of the cerebral cortex, it lists the functional areas but not the functions of those areas. Although it is stated in the video, which is a nice addition to the page, this could be improved by adding short sentences that state these functions that were mentioned as well. For Sections 1.4 and 1.5, references are also needed to state where the information was obtained from. The abnormalities section provides detailed explanations of the various disorders associated with the development of the cerebral cortex. There is also a good amount of pictures used. One thing I noticed was the references which was placed on the top of the section instead of throughout the text.

---

Overall, the page has a good structure and flow with good headings and subheadings. The information provided was concise and easy to comprehend. The introduction provides a brief overview and sufficient background knowledge about the cerebral cortex. I like how the team thought of mentioning about the early development of the brain before narrowing it down to the cerebral cortex. However these two sections do not seem to flow well. Maybe you could have 2-3 sentences that could help ease into the development of the cerebral cortex. I really love the timeline of corticogenesis. This part has been done really well. One minor improvement that could be made is to add images under each embryonic stage instead of just the last stage to better aid the reader into understanding the development. Also, a brief description of what corticogenesis is could be included before the table. For these two sections, there were a good amount of references.

For the anatomy of the cerebral cortex, it seems a little messy and hard to understand as its written in point forms. Perhaps, the dot points could be changed to proper sentences with histological images to tie it together. For the functions of the cerebral cortex, I think you could use a table to list down the areas and then provide a brief description of the functions of that particular part. The video is a good addition to the page. These two sections are lacking citations and references.The abnormalities section was well done. However, the citations should be added within the text instead of at the top of the page. Since there are a lot of abnormalities, maybe the team could list in a few sentences about all the abnormalities that they are going to discuss to have a better start to the section. For the images that are used on this page, the images should be labelled as “figure 1” or “table 1”. Maybe, sections on the “animal models” and “current research” could be added to wrap the page up.

----
Overall the project was very good and clear. Pictures were well placed and bullet points spaced out information, making the page easy to look at and follow. The layout of the beginning and end sections with the short paragraphs and interspersed bullet points broke up the information and highlighted key facts. The introduction was a good overview of the page, including a quick summary of the anatomy, function, and development of the cerebral cortex.

There were some basic grammatical and spelling errors (e.g. “neurons” is spelled wrong under the subheading “Layer 4”), but for the most part did not take away from the clarity of the page. One sentence, “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five,” seems to be missing something at the beginning that would increase clarity.

Some pictures had a lot of information in the summary when clicking on them while others lacked sufficient information. Some pictures that could benefit from more information are Corticogenesis of mouse and humans.jpeg, SBH.png, Disorders of Cortical Formation2.png, Symptoms of microcephaly.png, Hemimegalencephaly.png, and SchizencephalicBrain.jpg. These pictures are relevant to the topic and are pretty self-explanatory so this does not take away much clarity from the page but for the parameters of the project, additional summary should be added. The picture Stage22 HPA2L.jpg has good information in the summary but it is oddly structured. FASface.jpeg does not have any copyright information included. Having Gray754.png displayed on the page rather than as a link would look better.

The video describing the functions of the cerebral cortex was a good introduction to that topic. The video was easy to watch and understand. The first video about corpus callosum agenesis was a good introduction to the topic, but the second video about corpus callosum agenesis was long and the lecturer was hard to understand. That subheading would benefit from a brief description of that topic rather that a long video explanation.

The switch from a mix of bullets and short paragraphs to all bullet points in Anatomy of the Cerebral Cortex makes the page look less cohesive. The last bullet point in Layer 4 is hard to understand and the last 2 bullet points in Layer 5 would flow better if they were combined. The information in these sections are good and relatively easy to follow.

Overall the project is very good. The table explaining the timetable of cortex development is a clear way to break down the topic. Breaking down the information of abnormal development into what went wrong in the embryology (e.g. migration problems vs. differentiation problems) highlights importance of embryology in congenital disorders. There is a lot of information about the abnormal development of the cortex but could use some information about past and current research and animal studies. Reference list at the end looks good but the in-text citations of abnormal development should be interspersed with the information rather than all at the beginning.

----

The chosen headings for the development of the cerebral cortex were very suitable to highlight the key topics in providing a page of summarised information. It was then easy to navigate through the page using the shortcuts and finding information. Although, there was one sub sub heading “Timeline of Corticogenesis” that was formatted to be in bold while the rest were not.

The disorders listed seems to be really interesting and it covers the whole spectrum of the case abnormalities. But I suggest to get rid of the letter bullets (e.g. A), B), C) ) for the breakdown of the abnormalities.

The introduction had a quick and concise text, however, an image of the cerebellum would be suitable in this section on the side. While the sub sub heading stated that the introduction section will talk about the features of a cerebellum, a paragraph about the development and its stages were written down in this section as well. This could be moved into the ‘Early Development of the Brain’ subheading underneath. Bullet points of the brain layers as well as a diagram would be helpful for the visualisation of the brain.

For the sections that explain the development in specific weeks, a table would be advisable to make it neater and easier to look at. Also, an image was left inside the table grids and it was confusing whether it was meant to be there or not. Perhaps adding a photo gallery showing the stages at the bottom of the table would be better.

Hand drawn diagrams were really precise, neat and was very visually appealing. It was taking up all the space and unless it is intentional, I suggest to resize the drawing into a smaller one that fits the page as well as the accompanying text and content of the drawing.

The variety of visual aids were really entertaining and were referenced properly.

Finally, the reference list at the bottom of the page did not have a consistent format. It was mostly APA format however the others looked like a different format.

---

The most obvious flaw was the lack of polish in formatting of some of the page. Bullet points are only so useful when it comes to writing a wiki page, instead of taking notes. The page is unfinished, but, the content included especially in the "Development of Cerebral Cortex" and "Abnormalities associated with Cerebral Cortex Development" was extensive and well done. The large table that linked the development with the time period was very useful and the choice of bolding key words allowed the main idea in the paragraph to be quickly understood from a glance. The use of images very much enhanced the descriptions and checker-like the layout of the different abnormalities was refreshing. Some subheadings, such as the Anatomy and Function of the cerebral cortex, could be elaborated on but the overall structure of the page is logical and fluid, and the writing is clear and concise without being superficial.

--- 
Strengths: 
• The page has an excellent structure covering a broad variety of topics regarding the cerebral cortex. It was great to see how you also explored abnormalities associated with the cerebral cortex. Furthermore the use of various subheadings and headings related to cerebral cortex development meets criteria 1 and 2 of the assessment. 
• The presentation of the wiki page was excellent in that a variety of images, videos and tables were utilized. The use of such sources of information helps present information in a much more clear and concise manner, whilst also providing a thorough explanation to visual learners. Hence the wiki page has an element of teaching at a peer level (criteria 4 is satisfied). 
• A large number of references have also been included within the wiki page, a characteristic which helps increase the reliability of information presented. Furthermore, most sources are recent which another great characteristic. Thus, it appears that the group has satisfied criteria 3 for the assessment. 
• Each topic appears to show a significant amount of detail which is excellent. In addition, the use of images alongside the text is a great tool as the audience is able to better visualize the concept being described. 

Areas of improvement: 
• Although you have provided a variety of recent references, to improve you may avoid using sources as old as 1977 as results presented from this study may be outdated. 
• It was excellent that the functional areas of the brain were listed, however to improve you may wish to elaborate on the specific functions of these areas. You may also explore how abnormalities of these areas during development may impact upon the behaviour of the individual following birth 
• Whilst a variety of topics have been covered, you may wish to also describe the importance of signaling throughout the process of cortical development. For example, you may investigate different growth factors and receptors involved in the process. 
• Another possible improvement would be to perhaps include a timeline of different researchers who contributed to the in-depth understanding of the developing cortex that we have today. You may also describe what each researcher discovered. 
• In order to completely satisfy criteria 5, you may wish to conduct further research beyond the scope of formal teaching activities. For example you may explore the contribution of animal models towards our understanding of cortical development. 

----

This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The developmental origin of the cerebral cortex is addressed well under the sub-heading ‘Early development of the brain’.

The development timeline of the cerebral cortex is described clearly and in detail in the table of the ‘Timeline of corticogenesis’.

Abnormal development of the cerebral cortex and the associated conditions are covered in an immense amount of detail. The accompanying images and videos enhance the written information, as well as making it easier for the reader to comprehend. In addition, the sub-headings of this section compartmentalize the congenital diseases in a logical manner that highlights the link between abnormal development and specific diseases.
| There are several key topic areas missing from the page:
*There is no section covering key historical discoveries relevant to the cerebral cortex and its embryological development.
*There is no information relating to developmental signalling processes
*There is no section on current research in fields relevant to the embryological development of the cerebral cortex.
*There is no section on animal models that have been used to advance scientific understanding of the cerebral cortex.
*There is no section on future questions regarding the development of the cerebral cortex.
*A glossary of terms has not been included.

Some sections that have been included are somewhat irrelevant to the subject matter. For example, there is a large (unfinished) section on the anatomy and functions of the cerebral cortex. While it is important to provide a bit of an anatomical background on the subject, it shouldn’t be a major focus of this assignment. Focus more on the sections mentioned above, and keep the project focused on the embryology of the cerebral cortex.
|-
|2. Content is correctly cited and referenced
|There have been attempts at referencing throughout the assignment. A reference list has been produced and appears mostly correct. References have not been repeated throughout the list.

Peer-reviewed primary research articles have been used in this assignment.

The student-drawn image has been cited correctly, as have most of the images used in the ‘abnormal development’ section.
|Overall, referencing in this assignment is very poor. Most of the content is completely devoid of any references (see ‘introduction’, ‘anatomy of the cortex’ and ‘abnormal development), and sections that have been referenced have been referenced “by paragraph” (see ‘timeline of corticogenesis’)

Many of the sources used in this assignment are inappropriate and/or unreliable. Try to rely more on primary research articles and less on textbooks or websites.

Many of the images have been cited incorrectly and used without permission. Remember to include the full reference, the original summary and the copyright license information for each image.
|-
|3. The wiki has an element of teaching at a peer level
|The information presented is mostly at a level appropriate for peers. Images and hand-drawn diagrams have been included to facilitate the readers understanding of the subject matter. Some of the images contain useful descriptions of the subject matter, and aid in understanding of the topic.
|Many of the acronyms and terms used in this assignment are not well explained. Include a glossary of terms to make some of the content easier to follow and understand.
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The development of the cerebral cortex was covered extensively, which is a very important learning aim of embryology.
|There are certain learning aims of embryology that have not been included in this assignment, such as developmental signaling processes (see criteria 1 for more information). There has been no discussion of relevant historical or current research (adding in the subheadings “key developments” and “current research” would help rectify this).
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Certain aspects have been researched and presented well (such as embryological development).

Links to other pages of the UNSW embryology wiki have been included, however they have been used as references rather than just links.
|Information from the UNSW embryology wiki has been used as direct sources of information. Instead they should be included to relate this particular wiki page to other areas of learning.

The small number of sources cited in the reference list demonstrates a poor and narrow approach to researching this topic. A greater library of sources should be used to create this page (mainly primary research articles).
|}

Grade: FAIL

General Comment:
While some aspects of the wiki page have been done well, the page is largely unfinished. Many sections still need to be added, and others are in need of improvement.

----
The introduction of this page gives a good general background but could benefit from adding bullet points to describe the six horizontal layers of the cortex and maybe a short summary of its clinical significance. 'Early Development' was well written, easy to follow and well referenced. 'Development of Cerebral Cortex' would benefit from a short introductory statement instead of going straight into the 'Main classes of neurons'. Pictures and tables in this section were informative and engaging to the reader. Hand-drawn picture was well done, colourful and easy to interpret. 'Anatomy of the Cerebral Cortex' looks unfinished and isn't easy to read as it doesn't flow or show a clear structure. No references can be seen and no pictures or tables to make for easier reading or understanding. The different layers of the cortex would greatly benefit from a table with structure/function format or a clear diagram. The same is true for 'Functions of the Cerebral Cortex'. 'Abnormalities associated with Cerebral Cortex Development' I liked the setup of this section because of its clear headings and subheadings as well as its informative pictures. The captions on some of these pictures need to be elaborated on. Also couldn't see any in text referencing which really needs to be present. Content is clear and concise and easy to follow. This section was engaging and well done. 'INFO/Research Links' was not finished yet but shows lots of research articles that could be promising.
----

'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

----

User:Z5178275

2017-10-12T00:10:35Z

Z5178275:

{{ANAT2341ProjectGroup2017table}}

== Peer reviews ==

'''Peer review project 1:'''

I have some general comments which applies to almost all of the sections in the project:
* The referencing is not proper. A lot of the sections do not have reference or all of the reference are at the bottom of the section.
* Some of the sections have bullet points instead of text. It feels like you are reading somebodies notes not a project.
* It would be nice with more pictures to get a better understanding. The pictures there are good, but it does not have any caption. The size is to big as well for some of the pictures (the drawing with the mouse and human model)
* The project does not have a current research, future questions section or animal, which is a requirement for the project.
* I think it would be better for the project if the anatomy and function sections stood before the development part. It would give a better understanding or at least I think so.
* In general, I don’t feel like the project is connected, and expressions like cortigenesis and neurogenesis is not defined.
* I really think the timeline is nice. But a lot of the text within the timeline would have been more appropriate to write in the cortex development section. It should contain some key discoveries instead. But the text there is good, makes sense to me and is well written.
* In the early development of the brain section I don’t understand some of the sentence like: “From there three primary vesicles, there is a further division at the anterior extremity of the medullary canal into five secondary vesicles during week five. These are fundamental divisions of the adult brain and communicate freely with each other”. Some of it should properly be rephrased.
* There are some repetions during the project. The text could be compromised.
* In general, the language is neutral and written in a good scientific way.

'''Peer review project 3:'''

Some general comments to the project:
*The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project.
* Overall, I think the project was good. It was well written, easy to understand as a student, the sections correlated well and the context was good. I especially liked the signalling section, even though some context is missing. I think the idea of adding a treatment part to project is a good but I could not find it in the project. As mentioned some context is missing, which is the notch pathway, sonic hedgehog and retinoic acid sections.
* The project has a good introduction. You have a clear idea of what you are about to read, which is nice.
* The layout could be a lot better, I think the picture location could be adjusted. In the developmental origin part, the pictures make the section look very confusing. Some of the subheadings, like the abnormal development is pushed to side by the pictures, so when you scroll down the project you miss it.
* In general, the pictures miss their caption, sources and number. Therefore, you do not know which picture there is referred to when you are reading the project. I miss some more pictures in the developmental sections. Some of the home made drawing is not very descriptive
* In the developmental origin section I think the last sentence is very long. You get so much information in one sentence that you sometimes forget what you just read.
* The timeline is easy to read and understand. Could contain some key discoveries.
* Thought the glossary of terms is a nice addition to the project.
* Overall the referencing is good, but in some sections like primary heart field and heart tube formation, the referencing is missing. In some sections the articles/or links are at the bottom of the section, which makes it a little confusing.
* I don’t feel like the primary heart field and heart tube formation correlates very well with the secondary heart field and cardiac looping section. When I start reading the latter I feel like I am starting on something completely new instead of continuing reading on the heart developing. I get the feeling I am reading two different persons work, and some work should be put into these sections to make it feel more fluent.
* An idea for your project could be that you add a short anatomy section after the introduction, so the reader gets a picture and an overview of how the heart is structured. Then it is easier to understand the developing of the heart when you know how the heart is going to end up looking like.

'''Peer review project 4:'''
* The project does not feel like it is finished. A lot of work still needs to be done, and some of the subheadings like retina, cornea, eyelids, lacrimal glands etc is still empty.
* I did not find any sections describing signalling, research or future questions and animal models. I miss some more research content and a research angle to the project.
* The few parts of the development of the eye components which has been written was good. It was easy to understand and had good referencing.
* In general, the project could use more pictures to support the text.
* The anatomy part of the project was good. The drawing made it easier to understand, even though the picture captions and numbers are missing. I did not have any difficulties understanding it and they wrote it in a very clear way.
* I liked the overview of the eye development, it made it clear what is happening when, which cells comes from which germ layer and the Carnegie stage is a nice adding, even though it is not finished.
* The abnormal development section is far from finished. I think it is an important part of the project and it would improve the project if the anomalies where describe more in depth and not in a table.
* The glossary section was empty as well.

'''Peer review project 5'''

* The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project. But when you read the developmental origin section it does not say which germ layer it comes from. That is written in another section which I find confusing.
* Good idea drawing your own pictures, but because it is done with a pencil it is difficult to see what’s written on the picture.
* I like the anatomy introduction to the lungs – but I don’t see how the histology part is relevant to the project
* The abnormal development section was well-written and seemed like the group had done their research
* The current research section is still empty
* I liked the development timeline with the historical discoveries. But I think the development is the key stone of the project and therefore it would be nice if it had is own section instead of being the table. But the context itself was good
* I think the conducting system section is good and I like how you referred to the signalling processes which is also well described.
* Some sections still need referencing
* I liked that you included videos in your project

Here is the [[Student Page]] demonstration page I showed in the Practical class.

Use this page to practice editing and don't forget to add a topic to the [[2017 Group Project 2]] page.

[[File:Chicken embryo E-cad and P-cad gastrulation.png|500px]]

Chicken embryo E-cadherin and P-cadherin in gastrulation<ref><pubmed>27097030</pubmed></ref>

 
{{2017ANAT2341 footer}}

Talk:2017 Group Project 3

2017-10-12T00:07:58Z

Z5178275:

{{ANAT2341Project2017discussion}}



==Suggested Starting Places==
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 3 below are some starting places.

{{Heart Links}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Heart+Development ''Heart Development''] | [http://www.ncbi.nlm.nih.gov/pubmed?term=Cardiac+Development ''Cardiac Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Heart+Development ''Heart Development'']

Recent papers

<pubmed limit=5>Heart+Development</pubmed>

==Group Topic Intro==

=Peer Review=

'''Peer review project 3:'''

Some general comments to the project:
*The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project.
* Overall, I think the project was good. It was well written, easy to understand as a student, the sections correlated well and the context was good. I especially liked the signalling section, even though some context is missing. I think the idea of adding a treatment part to project is a good but I could not find it in the project. As mentioned some context is missing, which is the notch pathway, sonic hedgehog and retinoic acid sections.
* The project has a good introduction. You have a clear idea of what you are about to read, which is nice.
* The layout could be a lot better, I think the picture location could be adjusted. In the developmental origin part, the pictures make the section look very confusing. Some of the subheadings, like the abnormal development is pushed to side by the pictures, so when you scroll down the project you miss it.
* In general, the pictures miss their caption, sources and number. Therefore, you do not know which picture there is referred to when you are reading the project. I miss some more pictures in the developmental sections. Some of the home made drawing is not very descriptive
* In the developmental origin section I think the last sentence is very long. You get so much information in one sentence that you sometimes forget what you just read.
* The timeline is easy to read and understand. Could contain some key discoveries.
* Thought the glossary of terms is a nice addition to the project.
* Overall the referencing is good, but in some sections like primary heart field and heart tube formation, the referencing is missing. In some sections the articles/or links are at the bottom of the section, which makes it a little confusing.
* I don’t feel like the primary heart field and heart tube formation correlates very well with the secondary heart field and cardiac looping section. When I start reading the latter I feel like I am starting on something completely new instead of continuing reading on the heart developing. I get the feeling I am reading two different persons work, and some work should be put into these sections to make it feel more fluent.
* An idea for your project could be that you add a short anatomy section after the introduction, so the reader gets a picture and an overview of how the heart is structured. Then it is easier to understand the developing of the heart when you know how the heart is going to end up looking like.

---

Don’t forget to remove the hyperlinks that are under ‘Heart’ at the beginning of the page. Remove student numbers from the page. Add a brief description under images so that readers will understand what the image is showing. Remember to move references that are written in some sections to the ‘References’ subheading. The Notch Pathway is incomplete.

Subheadings and content that have been used show a good understanding of the topic area. The use of a table for the ‘Development Timeline’ shows the teams innovativeness. The use of simple sentences in the table allows readers to understand content simply. References have been done well, they are cited properly. The team have used their own images to show their understanding of the heart. The images that they have used have been properly cited: there are references, copyright statements and the Student Image template. Thorough description of abnormal development, animal models and current research which shows the comprehensive research that was done for the heart. The use of Glossary of Terms is helpful to readers who may not understand what some terms are.

---
Very informative and well written wiki. The glossary of terms is particularly useful and presented beautifully. The frequent addition of images and hand-made drawings are really good as they provide a useful visual reference point. The inclusion of a brief overview about the different animals studied in regards to the heart is very interesting. There is a minor spelling error in the table referring to Developmental timeline (week 5). The use of references is great, however maybe just include the links at the bottom of the wiki, to assist with the flow of information. Also add a description of your images so that viewers can more easily identify how the image relates to the text and the relevance of it. Overall, a really good wiki and well done.

----

The project is very good. There is a lot information on the page, there is a good description of each picture when you click on them, and there is a good brief introduction of each topic before going into depth on certain points. Most things are described clearly with pictures to support the information. Ending the project with a glossary of terms adds clarity to the project.

In particular, the “Developmental Signalling Processes” section is excellent. There is a description of where molecules are expressed, what cells they act on, the molecules’ roles in the cell signalling pathway on individual cells, and the molecules’ roles in overall heart development. The table describing different types of FGF signalling is excellent. In this section and throughout the project, there is a lot of description of research that has led to the discovery of the information presented on this page. The section “Animal Models” and “Current Research and Findings” add to this.

There are still a couple things to be fixed before the project is complete. There are some grammatical and spelling errors, particularly in “Proepicardium and Coronary Heart Development” that need to be edited. Some subheadings have nothing under them. Some references need to be fixed. Copyright information is needed when you click on some of the pictures. Instead of just using a paragraph style, emphasizing information by bolding specific words or using bulleted information may make the project easier to read and understand. Near the beginning of the project, a picture of the locations of the truncus arteriosus, bulbus cordis, primitive ventricle, and primitive atrium in the heart tube may add to the description of early development. In addition, a description of valve development could add to the project. Overall very good project.

---

Use of headings and subheadings break this complex developmental process in to understandable, clear sections.
The images chosen to reinforce the material are appropriate and I particularly like that time has been taken to draw a number of these.
There does seem to be an awful lot of information, and I wonder if this can be cut down at all. For example there is the section on signaling during development, which is a more complex section to understand. This is greatly helped by the diagrams but I can see that there are additional headings that are yet to have information added. It might be an idea to pick a few signaling pathways that occur and really perfect those. I think it has the potential to become very confusing to the reader otherwise.
It is very useful to the reader that you have included a glossary of terms, however I wonder if it may be more effective if this table is placed at the beginning of the page, or as a link at the top that can be opened up, so as the reader can familirise themselves with the terms prior to reading the page.
The page appears to be referenced extensively throughout and appropriately. Good job

---

Overall, this page has a good structure and was enjoyable to read. The headings and subheadings were clear and made it easier to understand the development process of the Heart. Perhaps it would be better to include relevant background information of the heart before jumping into the developmental process straightaway. There is a good amount of images (and well-drawn images) accompanying the text which aided in understanding the content, however some were not labelled with their appropriate descriptions. Most parts were cited correctly and properly, however some areas weren't cited at all such as "Current Research and Findings and "Cardiac Stem Cells". Also, some references were not done properly, check the "Primary Heart Field and Heart Tube Formation" section. Some sections were left blank, however I assume they will be completed over time. Glossary of terms was clever and made the content easier to understand (the heart is quite complicated to understand). Well done overall.

---

Overall, this page had a finished feel because the page is so heavily packed with information, there are some sections that were not completed. There is however, a lot of information that may leave the reader feeling a bit overwhelmed. Some sections are also hard to understand and comprehend especially due to the heavy use of biotechnological jargon (ie. SMAD-dependent, SMAD-independent pathways, β-catenin). A terminology/glossary section would be extremely helpful for this issue. I'd advise using more images in "Abnormal Development" (ie. x-rays or physical observations of sufferers) to help the reader visualise such abnormalities. Referencing under images should be moved to the references section and should be referenced using the '''''< ref >''' '''< / ref >''''' if in text. Overall, there is a lot of information, some of which is not necessarily important. I'd advise to cut down, make paragraphs more simple and straight to the point, and use images to help the reader visually understand and comprehend.

---

Introduction is very good and explains a lot. Under the heading “Primary heart field and heart tube formation” – the reference at the bottom should be removed.
Secondary heart field and cardiac looping: First sentence doesn’t really make sense, maybe switch it up a bit.
Under current research and findings you have labelled a figure figure 1, when it is not the first figure in your wiki page, seems a little confusing. Images also don’t have appriopriate copyright info, description and referencing. Also figure 2 is placed right in the middle of the sentence, maybe put it to the right so it doesn’t interrupt reading.
Information could be formatted better under the heading atrial septal defect! Maybe some subheadings for the different defects? Same goes with the ventricular septal defect, its easier to read when things are broken up. Glossary is very good!

All the information written on your page is very well written and easily understood.
Images could be labelled better, add a figure to each of them as when you are referring to figure 1 and 2 in your writing, the images aren’t labelled so its hard to tell what image you are referring to.
With references, I don’t like how there is a bunch at the end of some headings? Could be because you still need to read them but looks messy.
There is an overwhelming amount of information, so good job on doing so much research but it was quite tedious to read, not sure if this much information is needed? But it is very hard to fault your wiki page so this might be a bit picky.

---

The introduction is a brief and clear overview of the page. I liked how you acknowledged what your page will explore about the heart development. The “Developmental origin” subheading had good information and good diagrams in addition. However, I would adjust your layout a bit in this section so that the diagrams don’t look so awkward. You could do this by breaking down that second paragraph. The timeline provided a brief overview but I would also suggest adding another column for images. There is also a spelling error on week 5 – it says “srtats” where it should be “starts”.
As you go into “primary heart field and heart tube formation”, “secondary heart field and cardiac looping” and the next few sections, the references appear at the bottom of the sections. You should fix this so that they only appear in the reference list at the end. You could also probably bold “heart tube fusion”, “heart looping” and other terms in your developmental timeline since you explore them in depth.
The “developmental signalling process” subheading is very detailed. Since you also have a few more parts to complete into this section, it might be better to try to minimise some of the text. Your inclusion of current research is good and unique as you explore one paper in depth. However, I would suggest that you find another one or two. The “animal models” subheading should probably have a diagram or two of the referenced research papers if possible. Again with “abnormal development” subheading I would suggest some more images to see what these defects look like and possibly cutting down some text. In “future questions” you might also be able to provide a possible direction research might take to potentially answer this question. Also, you had a very good, long list of references.

---

The page goes through everything required for the project page. It would be nice if the pictures on the page have a figure number and a short title on the figures, so it is easier for the reader to understand what figure belongs to what part of the section. A figure number on the picture makes it able for the writer to refer to a specific picture. There is a good use of tables and self-drawn figures/picture. This makes the page clearer and more readable. There are some references on the page that needs a different formatting, so it is not fully viewed in the sections. It is important that the references are given right after the specific section and not at the bottom of the section.

*'''The Introduction''' section gives a good excitement for the reader before reading the page. This gives an idea of what information to expect from the page. A little section about the anatomy of the heart and a picture could give a better preparation for the reader to understand the developmental part of the heart.
*'''The Development Origin''' section has a bit confusing layout.
*I like that the '''Cardiac Neural Crest and Outflow tract''' sections have a self-drawn picture, but maybe you can draw it a bit clearer, so it is easier to read the writing and understand the figure There is no figure text on the page of the figure.
*'''Current Research And Findings, Animal Models and Abnormal Development:''' These sections have a bit of a messy layout. The context is good, but there I a lot of text and pictures kind of mingling into each other. You could make these sections more separate in the layout.
*'''The Glossary of terms''' helps the reader a lot.

---

The headings were all neat, concise and impressive. It successfully highlighted and sectioned the key topics in the development of the heart. The addition of the technical signalling pathways and the details of the development were well summarised with appropriate references in superscript format. There was a nice variety of visual resources, both hand drawn and externally sourced. Most images have their copyright approval and reference included perfectly, except "Figure 1 Morphological defects in CTCF mutant embryonic hearts" and "Figure 2 - defects of mitochondria in CTCF mutant hearts". There was a nice flow throughout the page through the use of effective paragraph sectioning. The table for the glossary of terms was really useful and neat.

Some of the images didn't have a box around it and these figures were not labelled, this should be easily changed in the edit mode. Some of the hand drawn images were somewhat unclear, due to the writing as well as the rough outline of the heart. Signatures should also be removed. The references were also retained in the bottom of the sections. It was a confusing because it wasn't next to any paragraphs that needed to be referenced. A reference was also repeated in this section.

''For example:''
"This image is based upon Robert H Anderson, Sandra Webb, Nigel A Brown, Wouter Lamers, Antoon Moorman Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks. Heart: 2003, 89(9);1110-8 PubMed 12923046

Robert H Anderson, Sandra Webb, Nigel A Brown, Wouter Lamers, Antoon Moorman Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks. Heart: 2003, 89(9);1110-8 PubMed 12923046

Marc Sylva, Maurice J B van den Hoff, Antoon F M Moorman Development of the human heart. Am. J. Med. Genet. A: 2014, 164A(6);1347-71 PubMed 23633400"

Finally, there is a great variety of reputable sources of information. The only thing that needs changing is that the reference list should be revised. Some were left as a link and the list were inconsistent with its reference format.

---

This wikipage had all the sections required for this assignment and the team was very detailed in their content. There was also a good amount of referencing. However for certain areas, the entire reference was there instead of just the number. Also, the student numbers should be removed from the page. There was also a good number of photos used and it was good that they had a mix between self-drawn images and images obtained online. However, a way that could improve the images would be to add a description or a caption under each figure so it's easier to know what the picture is about. Some photos in this article lacked description, reference and copyright information, so that could be added as well. For most of the article, I can see that the team carried out a great amount of research for this topic, however it was a little difficult to understand some parts as they were very lengthy and slightly too content heavy. For the developmental timeline, the use of a table was good but the information could be presented in a more concise manner and the headings could be slightly more prominent to make it more readable. The signalling processes was also very well researched but quite lengthy, perhaps a few main signalling pathways could be chosen instead. For the abnormal developments, each abnormalities were well researched on. Perhaps images could be added to show the abnormalities and also maybe one or two more defects would be good. Overall, I think this group did a great job in researching and providing information on this wikipage. Maybe with a bit of tweaking here and there to make it more concise and readable, this wikipage would make a really good project.

---

Well-structured page which seems to be quite detailed and long to read. The extensive use of subheadings make it a little harder to follow in some areas such as under “Developmental timeline”, where after the table the subheading “Primary Heart Field and…” appears to be a little misplaced or is lacking flow completely. Need to remove the student numbers from the page and also the two links under the initial “Heart” heading. In text referencing throughout the page seems to be consistent for the most part however, there are some areas where the correct format needs to be used (i.e., under “Wnt signaling” and “Cardiac Neural Crest and Outflow tract”). Some images do have a description of what is addressed however, many of them do not – this expansion would help with the overall reading experience as well as add further information for understanding. Overall, an extensive knowledge of the topic is well demonstrated through an attention to detail – but perhaps a more concise approach would add some clarity to the text.

---

The introduction was very good! I like how it introduced why the heart is so critical in early development, explained what you were going to discuss and where there would be gaps due to a lack of medical knowledge. The information in developmental origin and the developmental timeline is really great, however, I think you need to consider joining these two headings and not splitting them into one. You also state in developmental origin "as seen in figure two", however, none of your images have figure titles so I am not sure which figure you're actually referring to. The timeline is a good basic reference point, so I think it would be nice for it to be before the origin outline as it gives the basics which you then go into more detail about. I like that you put in the developmental signalling processes and then outlined each one of these, obviously the rest of those processes that have subheadings but no information just need to be finished. The current research is really interesting, again images just need a figure of some sort. The future questions section is a little confusing as I'm not sure if that's an area you're going to go into more depth over or if that's a future question you think research should look in to? So a clarification would be good. The glossary of terms is super helpful and all referencing looks good!

---

At first glance this project seems very detailed and lengthy. In my opinion, it could have too much text and maybe summarizing and condensing some sections could be beneficial. Collapsible windows or maybe more use of subheadings or dot points could be used to make the page clearer and less overwhelming. The diagrams and tables are very engaging and informative. However I do think the position and sizing of the diagrams could be improved to align it with the text better. The text and most of the diagrams seem to be well referenced. Another suggestion for this page would be to make the overall title of ‘Heart’ larger and clearer, perhaps include a diagram of the heart with the title to make it more attractive. The overall title should also be placed above the contents section.
Despite these suggestions, well done this page is very detailed and informative and you have clearly put a lot of work and effort into it.

---

Great detailing of the development and signaling processes involved, it really showed me that the group had extensive knowledge on this topic. In addition, there is a good balance of personal images (e.g. wnt signaling diagram) and web images which showed me that the group dedicated time to make sure the reader fully understood each aspect of the topic. Most images also are properly cited with copyright statements, references, and description (some are missing, but overall are done well). It was very helpful to include a glossary of terms at the end for the reader to refer to. An image for the cardiac looping steps would help to visualize steps. Information needs to be added for the notch pathway, sonic hedgehog, retinoic acid. While the detail is very informative, there is a lot of information and can be a little overwhelming. It might help to add more bullet points (with only essential information) or to edit some of the superfluous information. In addition, captions for the images would help so that the reader knows which image you’re referring to when referring to them in the text.

---
'Introduction' is clear and informative, well referenced and gives a good outline for the rest of the page. 'Developmental Origin' has a bit of a confusing set up.. pictures are seemingly scattered and need captions. The 'Morphology of the Heart tube formation' hand-drawn figure is almost an exact replica of the original.. not sure if this is allowed because they are so similar. 'Developmental Timeline' has a very brief table.. would benefit from a better description of each week of development. This section has a couple of random references that should be at the bottom. 'Developmental Signalling Processes' diagrams need captions. There is a lot of information here which is very detailed. 'Current Research and Findings' has good subheadings and picture use; pictures need to have copyright information and citations added. Very detailed with good references throughought. 'Future Questions' needs to be added to but has shown evidence of initial research into this area. 'Glossary of terms' is a very good idea that has not yet been shown in other group topics. Maybe look into researching how to link certain words in the article to redirect to the bottom of the page to the Glossary of terms for quick definitions? Some references also need to be properly cited in the 'References' section. Over all, really well researched with some sections needing a bit more work.
---

User:Z5178275

2017-10-12T00:05:32Z

Z5178275: /* Peer reviews */

{{ANAT2341ProjectGroup2017table}}

== Peer reviews ==

'''Peer review project 3:'''

Some general comments to the project:
*The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project.
* Overall, I think the project was good. It was well written, easy to understand as a student, the sections correlated well and the context was good. I especially liked the signalling section, even though some context is missing. I think the idea of adding a treatment part to project is a good but I could not find it in the project. As mentioned some context is missing, which is the notch pathway, sonic hedgehog and retinoic acid sections.
* The project has a good introduction. You have a clear idea of what you are about to read, which is nice.
* The layout could be a lot better, I think the picture location could be adjusted. In the developmental origin part, the pictures make the section look very confusing. Some of the subheadings, like the abnormal development is pushed to side by the pictures, so when you scroll down the project you miss it.
* In general, the pictures miss their caption, sources and number. Therefore, you do not know which picture there is referred to when you are reading the project. I miss some more pictures in the developmental sections. Some of the home made drawing is not very descriptive
* In the developmental origin section I think the last sentence is very long. You get so much information in one sentence that you sometimes forget what you just read.
* The timeline is easy to read and understand. Could contain some key discoveries.
* Thought the glossary of terms is a nice addition to the project.
* Overall the referencing is good, but in some sections like primary heart field and heart tube formation, the referencing is missing. In some sections the articles/or links are at the bottom of the section, which makes it a little confusing.
* I don’t feel like the primary heart field and heart tube formation correlates very well with the secondary heart field and cardiac looping section. When I start reading the latter I feel like I am starting on something completely new instead of continuing reading on the heart developing. I get the feeling I am reading two different persons work, and some work should be put into these sections to make it feel more fluent.
* An idea for your project could be that you add a short anatomy section after the introduction, so the reader gets a picture and an overview of how the heart is structured. Then it is easier to understand the developing of the heart when you know how the heart is going to end up looking like.

'''Peer review project 4:'''
* The project does not feel like it is finished. A lot of work still needs to be done, and some of the subheadings like retina, cornea, eyelids, lacrimal glands etc is still empty.
* I did not find any sections describing signalling, research or future questions and animal models. I miss some more research content and a research angle to the project.
* The few parts of the development of the eye components which has been written was good. It was easy to understand and had good referencing.
* In general, the project could use more pictures to support the text.
* The anatomy part of the project was good. The drawing made it easier to understand, even though the picture captions and numbers are missing. I did not have any difficulties understanding it and they wrote it in a very clear way.
* I liked the overview of the eye development, it made it clear what is happening when, which cells comes from which germ layer and the Carnegie stage is a nice adding, even though it is not finished.
* The abnormal development section is far from finished. I think it is an important part of the project and it would improve the project if the anomalies where describe more in depth and not in a table.
* The glossary section was empty as well.

'''Peer review project 5'''

* The project contained both developmental origin, timeline, signalling processes, current research and findings, animals model and abnormal development sections. The project therefore has all the sections which were a requirement for the project. But when you read the developmental origin section it does not say which germ layer it comes from. That is written in another section which I find confusing.
* Good idea drawing your own pictures, but because it is done with a pencil it is difficult to see what’s written on the picture.
* I like the anatomy introduction to the lungs – but I don’t see how the histology part is relevant to the project
* The abnormal development section was well-written and seemed like the group had done their research
* The current research section is still empty
* I liked the development timeline with the historical discoveries. But I think the development is the key stone of the project and therefore it would be nice if it had is own section instead of being the table. But the context itself was good
* I think the conducting system section is good and I like how you referred to the signalling processes which is also well described.
* Some sections still need referencing
* I liked that you included videos in your project

Here is the [[Student Page]] demonstration page I showed in the Practical class.

Use this page to practice editing and don't forget to add a topic to the [[2017 Group Project 2]] page.

[[File:Chicken embryo E-cad and P-cad gastrulation.png|500px]]

Chicken embryo E-cadherin and P-cadherin in gastrulation<ref><pubmed>27097030</pubmed></ref>

 
{{2017ANAT2341 footer}}

User:Z5178275

2017-10-12T00:05:15Z

Z5178275: /* Peer reviews */